Devices and methods for measuring viscoelastic changes of a sample

ABSTRACT

The present invention provides an apparatus for use in viscoelastic analysis, for example in coagulation testing of sample liquids, such as blood and/or its elements. In the apparatus for use in viscoelastic analysis, the rotating means are provided below the cup, pin and cup receiving element. The present invention further provides capacitive detection means and temperature control devices, which may be used in the apparatus for use in viscoelastic analysis. The present invention further provides a method of performing viscoelastic analysis, e.g. coagulation analysis, on a sample using the devices and apparatuses.

This application is a divisional of U.S. patent application Ser. No.16/478,533, filed Jul. 17, 2019, which is a national stage entry ofInternational Application No. PCT/EP2017/051660, filed Jan. 26, 2017,each of which is hereby incorporated by reference in its entirety.

The present invention relates to the field of viscoelastic analysis of asample, in particular to hemorheology, for example to the viscoelasticanalysis of blood and/or its elements, e.g. plasma and cells. Thepresent invention is directed to devices, including detection devicesand heating devices, and apparatuses for use in viscoelastic analysis,for example in coagulation testing of sample liquids, such as bloodand/or its elements. The present invention is further directed to amethod of performing such viscoelastic analysis, e.g. coagulationanalysis, on a sample, such as a test liquid.

Hemostasis is an essential physiological process that stops bleeding atthe site of an injury by blot clotting (coagulation) while maintainingnormal blood flow elsewhere in the circulation. Coagulation is triggeredin case of injuries or inflammations by either extrinsic or intrinsicfactors, e.g. tissue factor (TF) or Hagemann factor (F XII),respectively. Both cascades converge in a common mechanism resulting inthe activation of thrombin—which cleaves soluble fibrinogen to generateinsoluble fibrin. Fibrin fibers form a crosslinked fibrin mesh at thesite of an injury.

Thrombocytes (platelets)—which undergo a number of physiological changesduring the process of coagulation—are also implicated in the formationof the blood clot. Once the coagulation cascade has been triggered,thrombocytes aggregate between the fibrin mesh at the site of injury.Within limits, a lack of thrombocytes can be substituted by an increasedamount of fibrin or vice versa. This is reflected by the observationthat the thrombocyte counts as well as the fibrinogen concentrationvaries even within healthy patients.

Various tests of hemostasis have been developed to aid in identifyingpatients with hemostatic defects that could cause excessive bleeding.Such tests include thrombocyte counts or the determination of fibrinconcentration. However, whereas such tests provide information as to theavailability of thrombocytes or fibrin in sufficient amounts, they donot indicate whether thrombocytes, fibrin or other components of thecoagulation cascade are biologically active and effective—i.e.effectively support coagulation under physiological conditions. Othercommon tests such as the prothrombin time (Quick-test) or the partialthromboplastin time (PTT) work on blood-plasma exclusively and thereforerequire an additional step for preparation of the plasma—which istime-consuming and therefore unfavorable especially under POC (point ofcare) conditions.

“Viscoelastic methods” have been developed in an attempt to overcomethese problems. Said methods commonly determine the firmness of theforming blood clot (or other parameters dependent there on) in acontinuous fashion: from the formation of the first fibrin fibers untilthe dissolution of the blood clot by fibrinolysis. Blood clot firmnessis a functional parameter, which is important for hemostasis in vivo, asa blood clot must resist blood pressure and shear stress at the site ofvascular injury. It results from multiple interlinked processes:coagulation activation, thrombin formation, fibrin formation andpolymerization, platelet activation and fibrin-platelet interaction andcan be compromised by fibrinolysis. Thus, viscoelastic methods allow fordirectly or indirectly assessing all of these interrelated mechanisms.

All viscoelastic methods rely on common setup: the blood sample (andforming blood clot) is placed in the space between a cylindrical pin andan axially symmetric cup. During coagulation (which is typically inducedby the addition of one or more hemostasis activating factors), theforming fibrin scaffold creates a mechanical elastic linkage between thesurfaces of the cup containing the blood sample and the pin immersed inthe sample. Blood clot formation and—firmness is determined by assessingthe ability of cup and pin to move relatively to each other. Thereby,various deficiencies of a patient's hemostatic status can be revealedand used for proper medical intervention.

The first viscoelastic method was called “thrombelastography” (HartertH: Blutgerinnungsstudien mit der Thrombelastographie, einem neuenUntersuchungsverfahren. Klin Wochenschrift 26:577-583, 1948). Themeasurement apparatus (21) is depicted in FIG. 1 : the sample (1) isplaced in a cup (2) that is periodically rotated to the left and to theright by about 5°, respectively. A pin (3) is freely suspended by atorsion wire (4). When a blood clot is formed it starts to transfer themovement of the cup to the pin against the reverse momentum of thetorsion wire. The movement of the pin as a measure for the blood clotfirmness can be continuously recorded by optical detection means (5),such as light beam deflection, and plotted against time. For historicalreasons, the firmness is thereby quantified in millimeters.

Modifications of the original thromboelastography technique (nowadaysalso called thromboelastometry) have been described by Hartert et al.(U.S. Pat. No. 3,714,815), Cavallari et al. (U.S. Pat. No. 4,193,293),Do et al. (U.S. Pat. No. 4,148,216), Cohen (U.S. Pat. No. 6,537,819),and by Calatzis et al. (U.S. Pat. No. 5,777,215).

In a measurement apparatus (121) according to U.S. Pat. No. 5,777,215,the sample (101) is also placed within a cylindrical cup (102) as shownin FIG. 2 . However, the pin (103) is not plunged into the sample by atorsion wire, but by a metal shaft (106) that is fixed to a base plateby a ball bearing (107). The shaft (106) is periodically rotated by asensitive spring (108) around its vertical axis. The movement of the pinas an inverse measure for the clot firmness can be again continuouslyrecorded by optical detection means (105), such as light beamdeflection, and plotted against time. Since the cup cannot be filledwith the test liquid in measurement position, it is received by a cupholder that can be attached to the base plate of the measurement device.

The outcome of a typical measurement with setups according to FIG. 1 or2 is illustrated in FIG. 3 . One of the most important parameters is theclotting time (CT), i.e. the time between the time points of (i)(chemically induced) start of blot clotting and (ii) the formation ofthe first long fibrin fibers (indicated by the firmness signal exceedinga defined value). Another important parameter is the clot formation time(CFT), i.e. the time required for the clot firmness to increase from 4to 20 mm. The CFT thus gives a measure for the velocity of the bloodclot formation. The maximum clot firmness a (MCF), i.e. the maximumfirmness achieved by a blood clot during measurement is also of greatdiagnostic importance. Further parameters obtainable fromthromboelastographic measurement curves include the amplitude (A) at acertain time after CT (e.g., A10 is the amplitude 10 minutes after CT)and the lysis index (LI) in percent of amplitude reduction when comparedto MCF at a certain time after CT (e.g., LI45 is the ratio between A45and MCF in percent).

A general advantage of thromboelastometry as compared to common testssuch as thrombocyte counts, fibrin concentration or PTT and the like isthat the coagulation process and the change of mechanical properties ofthe sample are monitored as a whole. Thromboelastometry therefore doesnot only provide information about the availability of the components ofthe coagulation cascade (including thrombocytes, fibrinogen and otherfactors) in sufficient amounts but also indicates whether each componentis biologically active and effective. In order to determine the amountand function of each component, such as thrombocytes, fibrinogen andother factors involved in coagulation, individually, a number ofactivators or inhibitors specifically targeting each component iscommercially available. Accordingly, thromboelastometry allows toexactly determine at which point of a patient's coagulation system aproblem is located.

To this end, state-of-the-art thrombelastometers which allow forconducting of several measurements in parallel. Thereby, detailedinformation on the current status of the coagulation-situation of apatient can be obtained and, based thereon, an appropriate therapy canbe identified within a few minutes. Furthermore, the effects oftherapeutic agents interfering with the coagulation cascade—whetherintentionally or secondarily (e.g., as side effects)—can be tested invitro prior to their application to the patient.

This is of particular importance in case of patients struck by massiveblood loss as it often occurs in context with multiple traumata. Theblood of such patients often is diluted due to infusions which areadministered to replace the loss in volume. This leads to a decrease ofthe concentration of thrombocytes as well as coagulation factors such asfibrinogen.

Another important topic in this context is the determination of thefibrin networks contribution to the final stability of a growing bloodclot. This can be achieved by adding a thrombocyte inhibitor, e.g.Cytochalisch D, to the sample before measurement. That way the activityof fibrin becomes directly accessible.

A major problem in thromboelastometric measurements results fromdecreasing signal-to-noise ratios in case of a reduced blood clotfirmness of the evaluated sample. This typically occurs when patientsstruck by massive blood loss (e.g., in the case of multiple traumata)received infusions in order to replace the loss in blood volume. Theseinfusions dilute the patient's blood, resulting in a decreasedconcentration of thrombocytes as well as coagulation factors such asfibrinogen. Inhibition of individual factors of the coagulation cascadefor diagnostic reasons (as described above)—e.g. by adding a thrombocyteinhibitor such as Cytochalisch D in order to evaluate fibrinogenfunction and activity- or dilution with other agents can also lead to areduced blood clot firmness and therefore a decreased signal-to-noiseratio and a loss of measurement accuracy.

This loss of accuracy is based on the fact that under the circumstancesindicated above (e.g. dilution or addition of inhibitors of thecoagulation cascade), thromboelastometric measurement is performed atthe lower limit of sensitivity: the geometry of the standardizedelements of the thromboelastometric measurement apparatus (the outerdiameter of the pin typically being about 5.0 mm and the space betweencup and pin being about 1.0 mm) and the amount of blood sample used permeasurement were originally chosen to obtain the best signals whenmeasuring conventionally activated and non-diluted blood clots ofnon-pathologic blood samples. Such tests result in values for themaximum clot firmness (MCF) between 50 and 70 mm, which is the mostsensitively detected range of the method. When assessing pathologic,diluted or pre-treated blood samples, however, the maximum clot firmnesscan be considerably reduced. For instance, in blood samples treated withthrombocyte inhibitors, the blood clot is formed from fibrinogen only,resulting in MCF values between 15 and 25 mm for normal patients, whileMCF values well below 10 mm are typically observed in the case ofpathologic samples.

The general sensitivity level of viscoelastic tests (considering theactually well-established disposable geometry and the availableball-bearing technology for the axis that holds the pin) results inabout 2 mm test-to-test variations (standard deviation). As aconsequence, when measuring such samples with low amplitudes asmentioned above, the coefficient of variation easily exceeds 20%,rendering the definition of exact decision trigger values nearlyimpossible.

To achieve better accuracy, several approaches have been suggested inthe past. However, despite those approaches (or due to their majordrawbacks), the measurement setup used for viscoelastic testing of bloodsamples has not been changed much during the last 20 years. For example,U.S. Pat. No. 8,322,195 B2 discloses modifications of the geometry ofpin and cup in order to improve signal quality for low-amplitudesamples. This deviation from the widely used standard geometry, however,would require substantial regulatory efforts to become medicallyaccepted. Another approach is described in U.S. Pat. No. 8,383,045 B2and aims at improving the bearing technology for viscoelasticmeasurements, but it has not been introduced into the market so far.

Since a sufficient signal-to-noise ratio and measurement accuracy iscrucial for a reliable diagnosis and appropriate treatment (wherenecessary) it would be an important achievement to increase thesensitivity of thromboelastometric tests. Apparatuses currently employedfor thromboelastometric measurements typically rely on opticaldetections means that can be susceptible to soiling and/or vibrations,further decreasing measurement. In addition, detection and rotatingmeans in the state-of-the-art apparatuses are typically attached to thepin, thereby increase the weight load thereon—which further reduces theaccuracy of the obtained results, since such state-of-the-artapparatuses are quite susceptible to undesired interferences. There isthus a need in the art to provide means and methods that allow for amore accurate and reliable thromboelastometric measurement. Moreover,measurement apparatuses exhibiting an increased meantime between failure(MBTF) and requiring less service efforts and manufacturing costs at anenhanced usability are urgently needed.

In view of the above, it is the object of the present invention toovercome the drawbacks of current thromboelastic test devices andapparatuses as outlined above. Accordingly, it is an object of thepresent invention to provide an apparatus for measuring the coagulationcharacteristics of a test liquid, whereby the detection of the signal isi) less sensitive against dust or any other contaminations of thedetection system, or ii) less sensitive against aging effects of thedetection system components, and/or iii) cheaper to implement within adiagnostic device for medical use when compared to the currentlyavailable technologies. The improvements of the present invention takeinto account that any worsening of the signal quality due to higherweight load on the bearings (and correspondingly higher friction withinthe bearing) must be avoided or kept as small as possible to obtainmedically valuable data with high accuracy.

The improvements of the present invention further consider that otherdisadvantages of prior art devices as resulting from their detectiontechnologies—in particular, regarding complicated user handling ordeficient robustness of the device—are also avoided. In particular, theimprovements in the detection technology according to the presentinvention can be combined with substantial configuration changes of themeasurement setup, in particular as it is not required anymore to placethe bearing that is above the measurement cup. Moreover, the presentinvention also provides a temperature control unit having a very lowvolume. In summary, the present invention increases the degrees offreedom in constructing a measurement apparatus, and, thus, enables ameasurement apparatus, which is easy to handle and to operate.

This is achieved by means of the subject-matter set out below and in theappended claims.

Although the present invention is described in detail below, it is to beunderstood that this invention is not limited to the particularmethodologies, protocols and reagents described herein as these mayvary. It is also to be understood that the terminology used herein isnot intended to limit the scope of the present invention which will belimited only by the appended claims. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art.

In the following, the elements of the present invention will bedescribed. These elements are listed with specific embodiments, however,it should be understood that they may be combined in any manner and inany number to create additional embodiments. The variously describedexamples and preferred embodiments should not be construed to limit thepresent invention to only the explicitly described embodiments. Thisdescription should be understood to support and encompass embodimentswhich combine the explicitly described embodiments with any number ofthe disclosed and/or preferred elements. Furthermore, any permutationsand combinations of all described elements in this application should beconsidered disclosed by the description of the present applicationunless the context indicates otherwise.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the term “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated member, integer or step but not the exclusion of any othernon-stated member, integer or step. The term “consist of” is aparticular embodiment of the term “comprise”, wherein any othernon-stated member, integer or step is excluded. In the context of thepresent invention, the term “comprise” encompasses the term “consistof”. The term “comprising” thus encompasses “including” as well as“consisting” e.g., a composition “comprising” X may consist exclusivelyof X or may include something additional e.g., X+Y.

The terms “a” and “an” and “the” and similar reference used in thecontext of describing the invention (especially in the context of theclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. No language in the specification should beconstrued as indicating any non-claimed element essential to thepractice of the invention.

The word “substantially” does not exclude “completely” e.g., acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the invention.

As used herein, the term “viscoelastic” (in all its grammatical forms)is used interchangeably with the term “thromboelastic” (in all itsgrammatical forms). “Thromboelastic” or “viscoelastic” measurements ortests refer in particular to methods or apparatuses for testing theefficiency of blood coagulation.

The term “about” in relation to a numerical value x means x±10%.

Apparatus for Viscoelastic Analysis

The invention provides an improved apparatus for thromboelasticmeasurements and measurement methods exploiting these improvements. Theinventive apparatus has been designed to overcome the drawbacks ofstate-of-the art thromboelastic tests. It comprises several beneficialfeatures, which synergize to provide an improved overall measurementaccuracy. Specifically, the inventive apparatus and methods areenvisaged to have the following advantages of rendering thethromboelastic measurement: i) more accurate by reducing the weight loadon the bearings (and thereby friction within the bearing) ii) easier toaccess and handle and more robust due to the unique design of theapparatus, iii) less sensitive against the deposition of dust or anyother contaminations/soiling of the detection system, and/or iv) lesssensitive against aging effects of the detection system components,and/or v) cheaper to implement within a diagnostic device for medicaluse when compared to the currently available technologies. Due to itsnovel and improved design resulting in an increased measurementaccuracy, the inventive apparatus allows for evaluating “standard” bloodsamples, but also diluted (e.g. due to prior infusion) or pre-treated(e.g. with a thrombocyte inhibitor) blood samples and thereby opens upnew potentials in blood coagulation measurement.

In a first aspect the present invention provides an apparatus formeasuring the coagulation characteristics of a sample comprising:

-   -   a cup suitable for receiving the sample;    -   a cup receiving element providing (detachable) fixing for the        cup in measurement position;    -   a pin suitable to be dipped into said sample in said cup,        wherein the pin is rotational symmetric, the rotational symmetry        axis of the pin forms a vertical axis, and the pin is attached        to supporting means;    -   rotating means comprising a shaft, which extends along the        vertical axis, which is rotatable around the vertical axis, and        which is attached to the cup receiving element or to supporting        means for the pin, such that a rotation of the shaft causes a        rotation of the cup receiving element or of the supporting means        for the pin, and/or vice versa; and    -   detection means capable of detecting a rotation around said        vertical axis and/or variations in a rotation around said        vertical axis;

wherein the rotating means are provided below the cup, pin and cupreceiving element.

The sample to be evaluated by use of the apparatus according to thepresent invention is preferably liquid. Accordingly, it is also referredto herein as “liquid sample”, “sample liquid” or “test liquid”. Morepreferably the sample liquid comprises or consists of a biofluid (alsoreferred to as “body fluid”), i.e. a fluid originating from an organism,in particular a fluid originating from a human or an animal. Even morepreferably the sample liquid comprises or consists of blood, preferablywhole blood, or one or more of its elements/components, e.g. plasmaand/or cells. Particularly preferably the sample comprises or consistsof a human blood sample and comprises (whole) blood and/or blood plasma.

Optionally, the sample may further comprise one or more of the followingadditional components, e.g.,

(a) one or more activators of coagulation, including without limitation,

-   -   (i) extrinsic activators such as Tissue factor (TF, also        referred to as platelet tissue factor, factor III,        thromboplastin, or CD142);    -   (ii) intrinsic activators (e.g. celite, ellagic acid, sulfatit,        kaolin, silica, or RNA, or mixtures thereof);

(b) one or more inhibitors of coagulation, including without limitation,

-   -   (i) fibrinolysis inhibitors (e.g. aprotinin, tranexamic acid,        eaca, thrombin-activated fibrinolysis inhibitor, plasminogen        activation inhibitor ½, α2-antiplasmin, or α2-macroglobulin or        mixtures thereof);    -   (ii) platelet inhibitors (e.g. cytoskeleton inhibitors such as        Cytochalasin D or a GPIIb/IIIa antagonist, preferably Abciximab,        or mixtures thereof);    -   (iii) heparin inhibitors (e.g. heparinase, protamine or        protamine-related peptides and their derivatives, or other        cationic polymers, for example hexadimethrine bromide        (polybrene) or mixtures thereof);

(c) coagulation components; and/or

(d) other components, including calcium salts (e.g. calcium chlorideand/or calcium lactate and/or calcium gluconate), stabilizers (e.g.albumin or gelatin), or phospholipids (e.g. phosphatidylserine,phosphatidylethanolamine, phosphatidylethanolcholine or mixturesthereof).

Depending on the diagnostic aim, the above described additionalcomponents can be used either alone or in combination: For example, ameasurement with a combination of extrinsic activator and plateletinhibitor (e.g., Cytochalasin D) in the sample can be applied todetermine the activity of fibrinogen without platelet contribution inthe sample. Advantageously, the apparatus according to the presentinvention is capable of reliably determining the coagulationcharacteristics of a variety of different samples, in particular(pathogenic) blood samples or pre-treated or diluted blood sample thatexhibit an impaired coagulation capacity as compared to healthy,untreated and/or undiluted controls.

As used herein, the term “measurement accuracy” or “accuracy” is usedinterchangeably with the terms “measurement precision” or “precision”.“Accuracy” or “precision” is in particular discussed in terms of thestandard deviation (SD) and percent coefficient of variation (% CV).Standard deviation is a measure of the variability (scatter of amethod). Its normal distribution gives a bell shaped curve. The % CVdescribes the SD as a percent of the average value. The viscoelastictest apparatus of the invention preferably provides results with a SD ofless than 20%, more preferably of less than 15%, even more preferably ofless than 10%, and most preferably of less than 5%.

As used herein, the term “cup” (also referred to as “measurement cup”,“cuvette” or “test cell”) refers to a cup that receives the sample to bemeasured, in particular in the viscoelastic test (e.g., blood or bloodcomponents). Accordingly, the term “cup” refers in particular to ameasurement cup, such as a cuvette or a test cell, in particular to beused in coagulation testing, such as in viscoelastic measurement.Preferably, the cup has a cylindrical or tapered shape. The cup, inparticular the cylindrical or tapered cup, preferably comprises (i) anupper open end that allows insertion of a pin prior to a viscoelasticmeasurement; and (ii) a closed lower end designed to receive the sample.Preferably, the upper open end of the cup and the closed lower end ofthe cup have a circular shape. It is also preferred that the upper openend of the cup has a diameter from 5 to 10 mm. Moreover, it is alsopreferred that the diameter of the (circular) upper open end of the cupis not smaller than the diameter of the (circular) closed lower end.Preferably, the cup has a cylindrical shape, whereby the diameter of the(circular) upper open end of the cup and the diameter of the (circular)closed lower end of the cup are about the same size. It is alsopreferred that the cup has a tapered shape, whereby the diameter of the(circular) upper open end of the cup is larger than the diameter of the(circular) closed lower end of the cup. Preferably, the closed lower endof the cup has no sharp edge along the border to the (cylindrical)sidewall of the cup. Preferably, the closed lower end of the cup has aradius of at least 0.25 mm, more preferably of about 1 mm or more.

Preferably, the cup is a plastic cup, more preferably the cup is adisposable plastic cup. Preferably, the cup is made of a plasticmaterial that can be injection-molded. Preferably, the cup is made of aninjection-molding compatible polymer material. Preferred examplesthereof include polystyrene (PS), polymethyl methacrylate (PMMA), methylmethacrylate acrylonitrile butadiene styrene (MABS), polyamide (PA),polysulfone, polycarbonate (PC), polyethylene (PE), polypropylene (PP),or the like or any other suitable material which does not affectcoagulation activation before or after a possible sample treatment. Itis also preferred that the cup is not made of a material containingglass or metal, e.g. sheet metal and/or aluminum foil, more preferablythe cup does not contain any glass or metal, e.g. sheet metal and/oraluminum foil.

The cup receiving element is configured to receive and support said cup.The cup receiving element will therefore have a shape, which correspondsto the shape of the cup, for example typically a cylindrical shape or atapered shape. It will be readily acknowledged that in order to becapable of receiving and supporting the cup during viscoelasticmeasurement, the cup receiving element should have dimensions thatexceed those of the cup.

The cup receiving element provides fixing for the cup in the measurementposition. For example, the cup receiving element may have a shape, whichcorresponds to the outer shape of the cup, such that no further fixationmeans are required for fixing the cup in the measurement position.Alternatively, fixation means known in the art may be used. Preferably,the fixation of the cup in the cup receiving element is detachable, suchthat disposable cups can be used, which are typically discarded, e.g.after single use/measurement.

Preferably, the cup receiving element comprises an open top portion forreceiving the cup prior to a viscoelastic measurement, and a closedbottom portion. Preferably, the top portion and the bottom portion ofthe cup receiving element have a circular shape. It is also preferredthat the diameter of the (circular) top portion of the cup receivingelement is not smaller than the diameter of the (circular) bottomportion. Preferably, the cup receiving element has a cylindrical shape,whereby the diameter of the (circular) top portion of the cup receivingelement and the diameter of the (circular) bottom portion of the cupreceiving element are about the same size. It is also preferred that thecup receiving element has a tapered shape, whereby the diameter of the(circular) top portion of the cup receiving element is larger than thediameter of the (circular) bottom portion of the cup receiving element.The bottom portion of the cup receiving element may have a radius of atleast 0.30 mm, more preferably of about 1 mm or more, wherein saidradius exceeds the radius of the bottom portion of the cup to besupported by said cup receiving element.

Preferably, the cup receiving element comprises temperature controlmeans to control the temperature of the cup and/or of the sample. Forexample, the cup receiving element may be heated directly, e.g. byelectronic heating elements such as thermal resistors or Peltierelements. The cup receiving element may also be heated indirectly, e.g.by radiation from a remote heating source. To control the temperature ata certain level a thermal sensor may be used to measure the temperatureto which the heat source may then be adjusted. Such a thermal sensor maybe directly attached to the cup receiving element (e.g., a thermocoupleor a thermal sensitive resonance circuit), or be a remote thermal sensor(e.g., a pyroelectric sensor).

Preferably, the cup receiving element comprises a cup receiver forfixing the cup and fixation means for attaching the cup receiver to theshaft or to other portions of the apparatus, in particular to immovableportions of the apparatus. The cup receiver provides a fixation of thecup in a certain position, i.e. due to the cup receiver the cup cannotbe moved or rotated in its position. For example, the cup receiver maybe formed as a hollow cylinder with an inner diameter that is onlyslightly (e.g., 0.01 to 0.1 mm) greater than the outer diameter of thecup and the cup receiver may “receive” the cup by pushing the cup'slower end into the opening of the hollow cylinder. Alternatively, thecup receiver may also be formed by a squeezing mechanism, for example byproviding a spring force to the outer surface of the cup. In particular,the cup receiver is fixed/attached to the shaft or to other portions ofthe apparatus, in particular to immovable portions of the apparatus, byfixation means. The fixation means may be any fixation means known inthe art. For example, the fixation means may be a thread to screw thecup receiver on/to the shaft or to other portions of the apparatus, inparticular to immovable portions of the apparatus, or the fixation meansmay be, for example, a fit/fitting to press/attach the cup receiveron/to the shaft or to other portions of the apparatus, in particular toimmovable portions of the apparatus.

The term “pin” as used herein (also referred to as “measurement pin” or“probe”) refers to an element for performing a viscoelastic test (cf.FIGS. 1, 2, 4, 5, 11 ). Typically, for performing a viscoelastic testthe sample to be tested, e.g. a (whole) blood sample, is provided in themeasurement cup as described above. For the viscoelastic test, typicallya pin is dipped into the cup, thereby typically contacting the sample,e.g. a (whole) blood sample. Preferably, the pin is immerged into thesample, e.g. a (whole) blood sample. Preferably, the pin used to performthe viscoelastic measurement has a radius of similar size, preferably ofabout the same size, more preferably of the same size, along its outeredge between lower end and cylindrical sidewall as the cup has along itsinner edge between lower end and cylindrical sidewall (cf. FIGS. 4, 5,11 ).

The pin preferably comprises a pin neck (i.e. an elongated portion)connected to a pin head (i.e. a bulge portion suitable to be immersedinto the cup, the pin head typically having a larger diameter than thepin neck). It will be understood that the outer diameter of the pin headforming the sample contacting portion has to be smaller than the innerdiameter of the cup comprising the sample such that the pin head can beinserted into the cup. The pin is preferably made of a polymer material,for example of an acrylic or styrene polymer material, such as PMMA,MABS, ABS, PS, or any mixed co-polymer thereof or any other materialwhich does not affect coagulation activation before or after a possiblesample treatment.

As described above, during measurement, the pin is typicallydipped/immersed into the sample provided in the cup. Thereby, the pincontacts at least partially (i.e., at least the tip of the pin or thepin head) the sample. The detection of the characteristic parameters ofthe sample, e.g. the blood forming a clot, is typically based on the(mechanical) coupling of cup and pin which is established by theformation of, e.g., a clot (cf. FIG. 3 ). Typically, in the apparatusaccording to the present invention, either the pin is moved, preferablyrotated, whereas the cup is stationary at the beginning or staysstationary throughout the measurement—or the cup is moved, preferablyrotated, whereas the pin is stationary at the beginning or staysstationary throughout the measurement. After the formation of, forexample, a clot between cup (cuvette) and pin, the clot itself isstretched by the movement of the pin relative to the cup or of the cuprelative to the pin.

For example, the cup may rotate and the pin is stationary at thebeginning, but able to rotate as well. Upon clot formation in this casethe pin may typically start to rotate, which can be measured. In apreferred example, the pin rotates and the cup stays stationarythroughout the measurement, whereby upon clot formation the initialunrestricted rotation of the pin starts to encounter increasingimpedance as the clot strength increases, which is typically measured,e.g. by detection by an optical system.

To enable a rotation of the pin inside the cup or of the cup around thepin, the pin (and preferably also the cup) is rotational symmetric. Thismeans that in particular a (horizontal) cross section of the pin has arotational symmetric shape. Preferably, all horizontal cross sections ofthe pin have a rotational symmetric shape. More preferably, the pin hasa cylindrical or a tapered shape with an essentially circular crosssection. The rotational symmetry axis of the pin (i.e. the axis which isessentially perpendicular to the rotational symmetric, preferablyessentially circular, (horizontal) cross section) forms a vertical axis.

As used herein, i.e. throughout the present application, the terms“rotation” and “rotating” refer to the circular movement/moving aroundan axis/center, in particular around the vertical axis. The term“rotatable” refers to the capability to do so. Preferably, an rotatableelement is during normal use of the apparatus (i.e. without applicationof violent force) not moveable in any other direction and/or way, inparticular with the exception of very small movements, which do notnormally impair measurement accuracy. The terms “rotation”, “rotatable”and “rotating” refer to “full” rotations (around the complete 360°) andto partial rotations (not around the complete 360°, but only to a part(certain angle) thereof). A rotation may occur in one direction only orin both directions. The terms “rotation”, “rotatable” and “rotating” arethus understood to include “oscillation” and “oscillating”, i.e.alternately (partially) rotating back and forth around an axis (inparticular vertical axis), e.g. between two fixed positions.“Oscillation” and “oscillating” therefore refers in particular to a(small) angular back and forth rotation (e.g., +/−2.5°) around an axis.A “rotatable” element will therefore be understood as being capable offully or partially rotating, and fully or partially oscillating, asrequired for most viscoelastic tests. In particular, a complete (full)rotation of 360° around an (vertical) axis is not even required for mostviscoelastic tests—typically a partial rotation of, for example, +/−2.5°around a (vertical) axis (i.e., in both directions) is sufficient forviscoelastic testing. A partial rotation is also referred to herein assmall angular movement or as (partial) circular motion. Preferably, theangular range of the partial rotation or oscillation is (covers) no morethan 60°, preferably of no more than 30°, more preferably of no morethan 20°, even more preferably of no more than 10°, still morepreferably of no more than 5° and most preferably of about 2.5°.

The pin, preferably the pin neck, is attached to supporting means. Suchan attachment may preferably be detachable, such that the pin can beremoved, for example for cleaning of the pin. The attachment may befixed or movable. Preferably, the attachment of the pin to thesupporting means is fixed, i.e. if the supporting means are immobile,also the pin is immobile; and/or if the supporting means move/rotate thepin performs essentially the same rotation/movement.

As used herein “supporting means” refers to any means, which can be usedfor support, for example of the pin. Typically the supporting means forthe pin provide the attachment of the pin to the “body” of the apparatusaccording to the present invention. Accordingly, the design/shape of thesupporting means may depend on the overall design of the apparatus.

Preferably, the supporting means of the pin are immobile/immovable, suchthat preferably also the pin attached to the supporting means isimmovable, such that the pin is fixed in an immobile manner. Embodimentsof the present invention with such an immobile/immovable pin are alsoreferred to herein as “rotatable cup” embodiments, because in thoseembodiments typically the cup/cup receiving element will be (partially)rotatable. As used herein, “fixed in an immobile manner” means that theelement, e.g., the pin or the cup/cup receiving element, is fixed in aposition that substantially neither allows the element to move in arotational movement around the vertical axis, nor in any otherdirection. In this context, “substantially” means that minimal movementsof the element may not always be prevented, and that such minimalmovements may be tolerated in case they do not significantly reduce themeasurement accuracy of the apparatus. Specifically, the apparatusshould be able to evaluate pre-treated, pathologic and/or diluted bloodsamples with an adequate measurement accuracy (i.e. preferably with anSD of less than 20%, more preferably of less than 15%, even morepreferably of less than 10%, and most preferably of less than 5%). Forexample, for immovable/immobile/stationary attachment of the pin, anyimmovable/immobile/stationary part of the apparatus may be used, such as(a part of) the housing of the apparatus, e.g. a cover. Thus, thesupporting means for the pin are preferably configured as a cover. Forexample, the pin can be attached (fixed) to an upper plate of theapparatus in an immobile manner, e.g. via its pin neck.

Alternatively, the cup and/or cup receiving element can be attached toany immovable/immobile/stationary part of the apparatus, such as (a partof) the housing of the apparatus, e.g. an upper plate. Accordingly, thecup receiving element may be attached (fixed) in an immobile manner,e.g. by means of an upper plate comprising a suitable opening/aperturefor receiving the cup/cup receiving element, e.g. via its rim or thelike.

It is also preferred (in particular in the case of an immobile cup/cupreceiving element as described above, but also in general) that thesupporting means for the pin are (partially) rotatable, such thatpreferably also the pin is (partially) rotatable. Embodiments of thepresent invention with such an (partially) rotatable pin are alsoreferred to herein as “rotatable pin” embodiments. For such “rotatablepin” embodiments the supporting means for the pin is preferably a(curved) rod or tube or a frame. Preferably, the movable supportingmeans for the pin, in particular the frame, are made of a materialcomprising metal, more preferably they are made of metal. Preferably,the movable supporting means for the pin are a frame. As used herein theterm “frame” typically refers to a rigid structure formed of relativelyslender pieces (or a single piece) so as to surround an area. In otherwords, a “frame” is in particular an arrangement of connected/joinedrelatively slender elements, such as rods or tubes, or a singlerelatively slender element formed accordingly (such as a single curvedrod or tube), which forms a closed outline of an area. Preferably theframe has an essentially circular, ellipsoid, triangular, quadrangular,pentagonal, hexagonal, heptagonal, octagonal or any polygonal, or evenirregularly shape. Thereby, “essentially triangular, quadrangular,pentagonal, hexagonal, heptagonal, octagonal or any polygonal” inparticular also includes embodiments with rounded corners, such asrounded triangular, rounded quadrangular, rounded pentagonal, roundedhexagonal, rounded heptagonal, rounded octagonal shapes. Preferably, themovable/rotatable supporting means for the pin have (at least) abilateral symmetrical shape. Thereby, a steady and balancedmovement/rotation of the pin is ensured. More preferably, the frame hasan essentially rectangular shape, in particular a rounded rectangularshape (i.e. with rounded corners).

The apparatus according to the present invention further comprisesrotating means comprising a shaft, which shaft

-   -   extends along the vertical axis,    -   is rotatable around the vertical axis, and    -   is attached to the cup receiving element or to supporting means        for the pin, such that a rotation of the shaft causes a rotation        of the cup receiving element or of the supporting means for the        pin, and/or vice versa.

Accordingly, the rotating means provide a rotation to the cup receivingelement (and, thus, to the cup) or to the supporting means for the pin(and, thus, to the pin). To this end, the rotating means comprise ashaft, which is directly or indirectly attached to the cup receivingelement or to supporting means for the pin.

The shaft extends along the vertical axis and is rotatable around thevertical axis. Thus, the shaft is also referred to as a “rotatableshaft” herein. The shaft is typically disposed below the cup/cupreceiving element and the pin. The shaft is thus connected to thesupporting means for the pin or to the cup/cup receiving element(typically a cup receiving element which supports a (disposable) cupthat can be easily exchanged or refilled for each measurement), thusrendering either of both elements rotatable whereas the other element istypically fixed.

In the preferred “rotatable cup” embodiments of the invention, the shaftis connected to (attached to) (the bottom portion of) the cup receivingelement so as to transfer rotation/oscillation to/of said cup receivingelement around the vertical axis. In other words, the shaft ispreferably attached to the cup receiving element, in particular to thebottom of the cup receiving element, such that a rotation of the shaftcauses a rotation of the cup receiving element and/or vice versa. Theshaft is typically attached to (the bottom portion of) said cupreceiving element via its upper end. In those “rotatable cup”embodiments, the pin is preferably fixed in an immobile manner asdescribed above, e.g. via its pin neck, optionally to an upper plate orto a cover as described above. A preferred “rotating cup” embodiment isshown in FIG. 4 and described in more detail below.

In the preferred “rotatable pin” embodiments of the invention, the shaftis connected to the supporting means for the pin, so as to transferrotation/oscillation to/of said supporting means for the pin (and, thus,to the pin) around the vertical axis. In other words, the shaft ispreferably attached to supporting means for the pin, such that arotation of the shaft causes a rotation of the supporting means for thepin (and, thus, of the pin), and/or vice versa. In those “rotatable pin”embodiments, the cup/cup receiving element is preferably fixed in animmobile manner, such that the cup attached to the cup receiving elementis fixed in an immobile manner. optionally to an upper plate. Forexample, for immovable/immobile/stationary attachment of the cupreceiving element, any immovable/immobile/stationary part of theapparatus may be used, such as an upper plate or housing (part) of theapparatus. A preferred “rotating pin” embodiment is shown in FIG. 5 anddescribed in more detail below.

Rotation of the shaft is preferably achieved by an elastic couplingelement. Thus, the rotating means preferably comprise an elasticcoupling element, which provides a rotation to the shaft. In thiscontext to “provide a rotation to the shaft” means in particular to“cause a rotation of the shaft”. The shaft then transfers the rotationgenerated by the elastic coupling element (a) to the supporting meansfor the pin (and, thus, to the pin, preferably via the pin neck), or (b)to the cup receiving element (and, thus, to the cup); thereby allowingthe cup and/or the pin to rotate (or oscillate) relatively to eachother.

The rotating means provide a rotation to the cup receiving element (and,thus, to the cup) or to the supporting means for the pin (and, thus, tothe pin), so as to allow rotation of the cup receiving element (and,thus, of the cup) or of the supporting means for the pin (and, thus, ofthe pin) around the vertical axis, in particular in an angular range ofat least 1°, more preferably at least 2°, and more preferably at least4°.

Preferred examples of an elastic coupling element (which provides arotation to the shaft) include a spring wire, a piezo-electric bendingelement, or a field-based forcing element using an electric force (e.g.,applied by inducing a charge difference between a first capacitorelectrode attached to the shaft and a second capacitor electrodeattached to the base plate) or using a magnetic force (e.g., applied bygenerating a first magnetic field within the shaft or within a magneticelement attached to the shaft and a second magnetic field within amagnetic element attached to the base support member of the apparatus,such as a base plate).

Preferably, the elastic coupling element is a spring wire. If a springwire is used for generating a torque acting (rotation) onto the shaft,one end of the spring wire may be fixed to the shaft. Preferably, thespring wire is positioned (in a plane) below a (ball bearing) andessentially parallel thereto.

Preferably, the elastic coupling element is a piezo-electric bendingelement. If a piezo-electric bending element is present for generating atorque acting onto the shaft, one end of the bending element may befixed to the shaft and the other end may be fixed to the base supportmember of the apparatus, such as a base plate. The rotation may then begenerated by applying selective voltage changes to the piezo-electricbending element, which results in corresponding bending movements.

Preferably, the elastic coupling element is a field-based forcingelement using an electric force. If an electric force is used togenerate a torque acting (rotation) onto the shaft, one small, isolatedmetal electrode may be attached to the shaft with its plane extendingperpendicular from the shaft, and a second and third metal electrode maybe attached to the base support member of the apparatus, such as a baseplate, for example essentially parallel to (a part of) a detectionmeans, such as a (first) capacitor plate. The first electrode mayreceive a defined charge of electrons, e.g., by electrically connectingto a charge reservoir before each measurement starts. If the secondelectrode also receives a charge by being connected to an electronreservoir, a repelling force between both electrodes occurs. Since therepelling force is the lower, the longer the distance between bothelectrodes, the rotating movement of the shaft will stop at a certainpoint as defined by the charge size on both plates. If the charge isselected as such the first electrode is not yet touching the thirdelectrode when stopping, a counter movement can be induced by clearingthe charges on the second electrode and filling the third electrode witha similar amount of charges as the second electrode. By alternatingclearing and filling of charges onto the second and third electrodes,the required movement for thromboelastic measurements can be generated.

Preferably, the elastic coupling element is a field-based forcingelement using a magnetic force. If a magnetic force is used to generatea torque acting (rotation) onto the shaft, a (small) magnet may beattached to the shaft having a distance d to the axis and with itspermanent magnetic field (or at least a component of its permanentmagnetic field) tangentially oriented to the distance d. By applying anexternal magnetic field with controllable intensity and/or direction(e.g., a magnetic field induced by an electric current in a solenoidcoil) to the magnetic field of the magnet attached to the shaft, arotation in can be applied in both directions as required for athromboelstometric measurement.

To avoid friction problems caused by the rotation of the shaft relativeto adjacent fixed parts of the apparatus (for example in the basesupport member of the apparatus, if the rotatable shaft extends throughthe base support member), the rotating means preferably also contain abearing, preferably with low friction torque. In general, a bearing isan element that constrains relative motion to only the desired motion,and reduces friction between moving parts. Preferably, the bearing isselected from a roll bearing, in particular a ball bearing; a magneticbearing; and an air-lubricated bearing.

A roll bearing (also referred to as “rolling-element bearing” or“rolling bearing”) is a bearing which carries a load by placing rollingelements (such as balls or rollers) between two bearing rings calledraces. The relative motion of the races causes the rolling elements toroll with very little rolling resistance. Preferred roll bearingsinclude ball bearings and roller bearings.

A ball-bearing has inner and outer races between which balls roll. Inparticular, a ball bearing uses balls to maintain the separation betweenthe bearing races. The purpose of a ball bearing is to reduce rotationalfriction and support radial and axial loads. It achieves this by usingat least two races to contain the balls and transmit the loads throughthe balls. Preferably, one race is stationary and the other is attachedto the rotating assembly (e.g., a hub or shaft). As one of the bearingraces rotates it causes the balls to rotate as well. Because the ballsare rolling they have a much lower coefficient of friction than if twoflat surfaces were sliding against each other. Particularly suitable isradial groove ball bearing of small diameter, for example 3 to 5 mm.Other ball bearings like thrust ball bearings, or roller bearings canalso be employed.

Roller bearings typically have higher load capacity than ball bearings,but a lower capacity and higher friction under loads perpendicular tothe primary supported direction. Preferred examples of a roller bearinginclude a cylindrical roller bearing, a spherical roller bearing, a gearbearing, a tapered roller bearing, a needle roller bearing, and a CARBtoroidal roller bearing.

Cylindrical roller bearings use cylinders of slightly greater lengththan diameter.

Spherical roller bearings have an outer ring with an internal sphericalshape. The rollers are thicker in the middle and thinner at the ends.Spherical roller bearings can thus accommodate both static and dynamicmisalignment.

A gear bearing is a roller bearing combining to epicyclical gear,wherein each element of it is represented by concentric alternation ofrollers and gearwheels with equality of roller(s) diameter(s) togearwheel(s) pitch diameter(s). The widths of conjugated rollers andgearwheels in pairs are the same. The engagement is herringbone or withthe skew end faces to realize efficient rolling axial contact.

Tapered roller bearings use conical rollers that run on conical races.Most roller bearings only take radial or axial loads, but tapered rollerbearings support both radial and axial loads, and generally can carryhigher loads than ball bearings due to greater contact area.

Needle roller bearings use very long and thin cylinders. Often the endsof the rollers taper to points, and these are used to keep the rollerscaptive, or they may be hemispherical and not captive but held by theshaft itself or a similar arrangement.

CARB bearings are toroidal roller bearings and similar to sphericalroller bearings, but can accommodate both angular misalignment and alsoaxial displacement. Compared to a spherical roller bearing, their radiusof curvature is longer than a spherical radius would be, making them anintermediate form between spherical and cylindrical rollers.

A magnetic bearing is a bearing that supports a load using magneticlevitation. Magnetic bearings support moving parts without physicalcontact. For instance, they are able to levitate a rotating shaft andpermit relative motion with very low friction and no mechanical wear.Magnetic bearings support the highest speeds of all kinds of bearing andhave no maximum relative speed.

An air-lubricated bearing (also referred to as “air bearing”,“aerostatical bearing” or “aerodynamical bearing”) is a bearing thatuses a thin film of pressurized air to provide an exceedingly lowfriction load-bearing interface between surfaces. The two surfaces donot touch. As they are contact-free, air bearings avoid the traditionalbearing-related problems of friction, wear, particulates, and lubricanthandling, and offer distinct advantages in precision positioning, suchas lacking backlash and static friction, as well as in high-speedapplications.

Roll bearings, in particular ball bearings are more preferred. Mostpreferably, the rotating means comprise a ball bearing. Particularlysuitable is a deep groove ball bearing of small diameter, for example 3mm. The use of a ball bearing has the advantage of reducingsusceptibility to shocks and vibrations. The bearing preferablyfunctions as frictionless as possible.

The rotating means can in principle be configured also in any otherways, as long as they are capable of generating a rotation. Saidrotation is then transferred via the rotatable shaft to either the cupreceiving element and, thus, to the cup (“rotating cup” embodiments); orto the supporting means for the pin and, thus, to the pin (“rotatingpin” embodiments).

In apparatuses for measuring blood coagulation characteristics known inthe art, the rotating means (e.g. the elastic coupling element and/orthe (ball) bearing) are typically disposed in the upper part of theapparatus, in particular above the pin (cf. U.S. Pat. No. 5,777,215 A),thereby placing an additional weight load on the pin, which rendersmeasurements inaccurate. Viscoelastic measurements rely on the detectionof even small changes in the angular movement of the pin or cup.Therefore, any additional weight load placed on the pin severely impairsmeasurement accuracy. In order to overcome this problem, the presentinventors developed an apparatus for measuring coagulationcharacteristics, wherein the rotating means are provided below the cup,the pin and the cup receiving element. For example, the rotating meanscan be disposed above, below or within a base support member.Preferably, the elastic coupling element is disposed above or below thebase support member of the apparatus. Preferably, the bearing, inparticular the ball bearing, is disposed in the base support member,such as a base plate, of the apparatus. It is also preferred that therotatable shaft extends through the base support member, in particular,the rotatable shaft extends through the base support member and throughthe bearing disposed therein. In this way, the (fixed) base supportmember bears the rotatable shaft without (or nearly without) anyfriction problems caused by the rotation of the shaft.

In “rotatable pin” embodiments it is preferred that the cup receivingelement is attached (fixed) in an immobile manner in an upper plate ofthe apparatus, which comprises a suitable opening/aperture for receivingthe cup/cup receiving element, e.g. via its rim or the like, asdescribed above. In such embodiments the pin is typically attached tothe supporting means for the pin (e.g., the frame as described above)above the upper plate of the apparatus, whereas the shaft—and other(optional) components of the rotating means—is/are disposed below thecup, cup receiving element and pin and, thus, below the upper plate.Since in such “rotatable pin” embodiments the supporting means for thepin connect the pin (above the upper plate) with the shaft/rotatingmeans (below the upper plate), the supporting means in such embodimentstypically extend through the upper plate. To this end, it is preferredthat the upper plate comprises suitable openings, which enable a(partial) rotation of the supporting means extending through the upperplate. Such a suitable opening may, for example have a round shape (likea segment of a circle) to enable partial rotation. For bilaterallysymmetrically frames two such openings may be provided in the upperplate. In this context it is particularly preferred that angular rangeof the partial rotation or oscillation is (covers) no more than 60°,preferably of no more than 30°, more preferably of no more than 20°,even more preferably of no more than 10°, still more preferably of nomore than 5° and most preferably of about 2.5°, such that thecorresponding openings in the upper plate can be relatively small tokeep the upper plate as stable as possible and to receive the cup/cupreceiving element.

The apparatus according to the present invention further comprisesdetection means capable of detecting a rotation around the vertical axisand/or variations in a rotation around the vertical axis. In the contextof coagulation characteristics it is most important that the detectionmeans can used to determine variations in the rotation around thevertical axis. In particular, the formation of a blood clotcounteracts/“impairs” the rotation as provided by the rotation means.For example, the rotation may be delayed and/or an increased “force” maybe required to maintain rotation.

Preferably, the detection means are selected from optical, electrical,or magnetic detection means. Preferably, the detection means areelectrical detection means; more preferably, the electrical detectionmeans are capacitive detection means, for example as described herein.Electrical detection means can be provided, for example, by implementinga capacitive sensor that detects changes of the electrical fieldstrength as induced by electrical conductor plates attached to thevertical axis and moved by axis rotation. Preferably, the detectionmeans are magnetic detection means. Magnetic detection means can beprovided, for example, by implementing a magnetic sensor that detectschanges of the magnetic field strength as induced by magnets attached tothe vertical axis and moved by axis rotation.

Preferably, the detection means are optical detection means, preferablycomprising a light emitter (such a light source, for example for visiblelight) and a light sensor (e.g., a photo sensor which is able to detectthe emitted light, i.e. which is typically sensitive for thecorresponding wavelength range). Preferably, the optical detectionsystem further comprises a mirror, in particular which may be mounted tothe pin (e.g., to the pin neck; or to an element connected to the pin,e.g., a “prolongation” of the pin/pin neck). The mirror can be used forreflecting a light beam from a light source towards a photo detectorsuch that the rotational position of the shaft of the pin is detectable.Such optical detection means are for example described in U.S. Pat. No.5,777,215 A.

The detection means are preferably disposed below the pin, the cup andthe cup receiving element, thereby avoiding any additional weight loadon the pin. The detection means are preferably disposed within or belowthe base support member, e.g. the base plate, of the apparatus. Thedetection means are preferably connected to the, in particular to itslower end.

Preferably, the detection means comprise one or more capacitor elements.In other words, it is preferred that the detection means are capacitivedetection means. Capacitive detection means are based on capacitivecoupling. Capacitive coupling is the transfer of energy within anelectrical network or between distant networks by means of displacementcurrent between circuit(s) nodes, induced by the electric field.Preferably, such an capacitor element comprises an electricallynon-conductive support, which preferably extends essentiallyperpendicularly to the vertical axis of the apparatus and at least oneelectrically conductive and rotatable layer disposed on the support,which preferably rotates with the same angular amplitude as the shaft.Preferred examples of the electrically non-conductive support and of theat least one electrically conductive and rotatable layer disposed on thesupport are described below in the context of the capacitive detectionmeans according to the present invention. Furthermore, it is alsopreferred that the detection means further comprises an electricalcircuit capable of detecting a rotation of at least +/−2° with anaccuracy of at least 0.2° on a time frame of at most 5 seconds asdescribed below in the context of the capacitive detection meansaccording to the present invention.

Capacitive Detection Means

In a second aspect the present invention provides a capacitive detectionmeans for detecting variations in a rotation around a vertical axiscaused by blood coagulation. Usually, apparatuses for viscoelasticmeasurement employ optical detection means, i.e. typically a mirrormounted to the pin for reflecting a light beam from a light sourcetowards a photo detector such that the rotational position of the shaftof the pin is detectable. While such optical detection means arecombinable with the apparatus according to the present invention asdescribed above, they may also exhibit certain disadvantages. Inparticular, such optical detection means are more prone to measurementerrors due to deposition of dust or other contaminants on the mirror.Such disadvantages are overcome by the capacitive detection meansaccording to the present invention.

Accordingly, the present invention provides a capacitive detection meansfor detecting variations in a rotation around a vertical axis caused byblood coagulation comprising

-   -   a rotatable capacitor element capable of rotating around the        vertical axis;    -   at least one fixed capacitor element; and    -   an electrical circuit, which is preferably connected to the at        least one fixed capacitor element;    -   wherein (i) each of the capacitor elements comprises at least        one electrically conductive element, which does not have a        circular shape with the vertical axis as center, and (ii) the        rotatable capacitor element and the at least one fixed capacitor        element are arranged such that the electrically conductive        element(s) of the rotatable capacitor element face the        electrically conductive element(s) of the at least one fixed        capacitor element.

In general, the electrically conductive elements of the rotatablecapacitor element and of the fixed capacitor element, which face eachother, function in a similar manner as the two conductive plates of aparallel-plate capacitor. To detect a rotation of the rotatablecapacitor element relative to the fixed capacitor element, theelectrically conductive elements of the capacitor elements can have anyshape, except for a circular shape with the vertical axis (i.e. therotation axis) as center. The reason is that a rotation (or a variationin the rotation) can be detected by a variation in the capacitance (orby charge fluctuation). Due to their shape (which is not a circularshape with the rotation axis as center), the distance between theelectrically conductive elements of the rotatable capacitor element andof the fixed capacitor element changes during rotation, which results ina variation in the capacitance.

However, it is also conceivable that the at least one electricalconductive element on the first capacitor element merely provides an“electric environment” for at least two (capacitor) electrodes(electrical conductive elements), which are located on the second (i.e.on the other) capacitor element. Again, rotation of one electricallyconductive element relative to the other induces capacitancedifferences/charge fluctuations, although in this case they are inducedby a change in the electrical environment due to the rotation. In such aconfiguration it is preferred that grounded electrodes are locatedbetween the at least two (capacitor) electrodes (electrical conductiveelements), which are located on the second (i.e. on the same) capacitorelement, in order to minimize direct capacitive charge variations amongthose electrodes located on the same capacitor element.

In general, such a configuration using an “electric environment” asdescribed above has the advantage that the electrical circuit needs onlyto be connected to one single capacitor element (on which the(capacitor) electrodes are disposed, i.e. the “second” capacitorelement). If the electrical circuit is only connected to one singlecapacitor element (on which the (capacitor) electrodes are disposed,i.e. the “second” capacitor element) it is preferred that this is thefixed capacitor element. This has the advantage that the rotatablecapacitor element can rotate “freely”.

As used herein the term “capacitor element” refers to an element, whichis in particular required to form a capacitor, i.e. one or morecapacitor elements can form a capacitor. The minimum requirements for acapacitor are two electrically conductive elements (and a dielectricbetween them, which may simply be air). Accordingly, a capacitor elementtypically comprises at least one electrically conductive element.

As outlined above, the electrically conductive elements of the capacitorelements can have any shape, except for a circular shape with thevertical axis (i.e. the rotation axis) as center. Accordingly, theelectrically conductive elements of the capacitor elements may have theshape of a spot, a quadrangle such as a square or a triangle, a circle(having a center which is not the rotation axis), a segment of a circle,or an ellipse. Most preferably the electrically conductive element(s) ofthe capacitor elements have essentially the shape of circle segments orblunt circle segments, for example as shown in FIG. 8A-D. It is alsoparticularly preferred that the electrically conductive element(s) ofthe capacitor elements have essentially the shape of a triangle orquadrangle (e.g., a rectangle, square or trapezoid), for example asshown in FIG. 9 .

One single electrically conductive element may comprise (or form) one ormore (capacitor) electrodes. Preferably, one single electricallyconductive element forms one single (capacitor) electrode.

Preferably, the electrically conductive elements comprise (morepreferably they are made of) a material having an electric conductivityof at least 5·10⁴ S/m. Although such conductor materials include metals,electrolytes, superconductors, semiconductors, plasmas and somenonmetallic conductors such as graphite and conductive polymers, solidconductor materials are generally preferred for the electricallyconductive element. Preferred examples of such solid conductor materialsinclude metals (most preferably copper, silver and aluminium) and metalalloys; superconductor materials such as metallic superconductors (e.g.magnesium diboride), A15 phases (e.g. vanadium-silicon,vanadium-gallium, niobium-germanium, and niobium-tin), and ceramic andiron-based superconductors (e.g. La_(1.85)Ba_(0.15)CuO₄, and YBCO(Yttrium-Barium-Copper-Oxide)); semiconductors such as silicon,germanium, gallium arsenide, silicon carbide, gray tin, gray selenium,tellurium, boron nitride, boron phosphide, boron arsenide, and the like;and graphite. More preferably, the material comprised by theelectrically conductive element (preferably, of which the electricallyconductive element is made of) is a metal, a metal alloy, ametal-containing material such as conductive silver paste, graphite,graphene, a conductive polymer (e.g., polyaniline or doped polypyrrole),or a doped semiconductor with increased conductivity (e.g.,phosphor-doped silicon or arsenic-doped germanium), or any combinationthereof.

“At least one” fixed capacitor element means one or more fixed capacitorelements, however, exactly one single fixed capacitor element ispreferred.

The rotatable capacitor element capable of rotating around the verticalaxis (i.e. the axis around which a rotation is to be detected), whereasthe at least one fixed capacitor element is fixed, i.e. stationary. Tothis end, the rotatable capacitor element can preferably be attached toa shaft of an apparatus for measuring the coagulation characteristics ofa sample, which shaft is rotatable around the vertical axis (andpreferably extends along the vertical axis), such that a rotation of theshaft causes a rotation of the rotatable capacitor element and/or viceversa. Preferably, the rotatable capacitor element has a “balanced”shape to enable steady rotation (i.e., without imbalance) around thevertical axis. The fixed capacitor element may then be attached to anystationary/immobile component of the apparatus, for example such that itis essentially in parallel to the rotatable capacitor element.

The rotatable capacitor element and the at least one fixed capacitorelement are arranged such that the at least one electrically conductiveelement of the rotatable capacitor element faces the at least oneelectrically conductive element of the at least one fixed capacitorelement. This means that in at least one rotation position of therotatable capacitor element the at least one electrically conductiveelement of the rotatable capacitor element faces the at least oneelectrically conductive element of the fixed capacitor element.Preferably, in such a face-to-face rotation position, there is no(solid) element/component between the electrically conductive element ofthe capacitor elements facing each other. More preferably, in such aface-to-face rotation position, there is nothing (except air) betweenthe electrically conductive element of the capacitor elements facingeach other. Preferably, in such a face-to-face rotation position, thedistance between the at least one electrically conductive element of therotatable capacitor element and the at least one electrically conductiveelement of the fixed capacitor element does not exceed 10 mm, morepreferably said distance does not exceed 7 mm, even more preferably saiddistance does not exceed 5 mm, and most preferably said distance doesnot exceed 3 mm.

Preferably, the at least one fixed capacitor element is arrangedessentially in parallel to the rotatable capacitor element. As usedherein, “essentially parallel” “essentially in parallel” and similarexpressions do not only include an exactly parallel orientation, butalso deviations (from exactly parallel) of up to 15°, more preferably upto 10°, even more preferably up to 8°, still more preferably up to 5°and most preferably up to 2°. Particularly preferably, the deviation(from exactly parallel) is up to 1°. Such deviations are tolerable,since they do not impair the capacitor functionality of the twocapacitor elements. In view thereof, the angle between the two capacitorelements is preferably not changing over time. If the angle between thetwo capacitor elements changes over time (e.g., due to tilting duringrotation), the more complex electrode geometries described below arepreferred.

As outlined above, the electrical circuit is preferably connected to theat least one fixed capacitor element, in particular to the at least oneelectrically conductive element of the fixed capacitor element. Such aconnection may be configured as a cable, wire or the like. Morepreferably, there is no cable or wire connection to the rotatablecapacitor element. In this case, the fixed capacitor element comprisespreferably at least two (capacitor) electrodes.

The electrical circuit typically comprises at least one voltage source,for example a frequency generator, and, preferably, a detector fordetecting capacitance differences by corresponding charge fluctuations,for example a charge amplifier circuit (also referred to as “currentintegrator circuit”). Preferably, the electrical circuit furthercomprises one or more filters, e.g. low-pass filters, to reduce noise(i.e., to increase the signal-to-noise ratio), which is/are preferablyarranged after the detector in the electrical circuit.

In a preferred embodiment, the voltage source provides an alternatingvoltage to at least two (capacitor) electrodes (“first” and “second”electrode) located on a first capacitor element (e.g., on the fixedcapacitor element), thereby inducing charge fluctuations on bothelectrodes, and, due to a capacitor effect, also at a third (capacitor)electrode located on the same (e.g., fixed) capacitor element or on adifferent (second) capacitor element (e.g., on the rotatable capacitorelement). For example, if said three capacitor electrodes are located onthe same (e.g., fixed) capacitor element, the fluctuations on the third(capacitor) electrode depend on the electric environment around the twoelectrodes, to which voltage is provided. The electric environmentchanges significantly by rotating the conductive element(s) of the other(e.g. rotatable) capacitor element. The charge fluctuations on the thirdelectrode may optionally be amplified by a charge amplifier. A detectorconnected to the third (capacitor) electrode (or to the amplifier, ifpresent) can then detect charge fluctuations induced by the rotation.Preferably, the detector is a synchronized detector, which is capable todetect the charge fluctuations on the third (capacitor) electrodesynchronously to the initial voltages provided to the first and secondelectrode. Thereby, two voltages U₁ and U₂ are generated, which maysubsequently be optionally send through separated low-pass filters toreduce noise. Both (filtered or non-filtered) voltage signals, U₁ andU₂, allow calculation of a signal proportional to the angulardisplacement D of the rotatable capacitor element by D=(U₁−U₂)/U₁+U₂).To provide this signal as recordable data stream, the initial signals U₁and U₂ can optionally also be digitized in an ADC (analog/digitalconverter) and then further processed digitally.

Preferably, the electrically conductive elements have an area size of atleast 25 mm², more preferably at least 35 mm², even more preferably atleast 42 mm², and most preferably at least 50 mm². It is also preferredthat the distance between the fixed and rotatable capacitor elements isno more than 2 mm, more preferably no more than 1.5 mm, even morepreferably no more than 1 mm. It is also preferred that theexcitation/detection voltage frequency is at least 1 kHz, preferably atleast 2 kHz, more preferably at least 5 kHz. Thereby a rotation of therotatable capacitor element around the vertical axis can be detectedquickly and with high accuracy.

For example, if all three conditions are fulfilled, i.e. if theelectrically conductive elements have an area size of at least 25 mm²,the distance between the fixed and rotatable capacitor elements is nomore than 2 mm, and if the excitation/detection voltage frequency is atleast 1 kHz, the electrical circuit will be capable of detecting arotation of the rotatable capacitor element around the vertical axis ofat least +/−2° with an accuracy of at least 0.2° in a time frame of atmost 5 seconds. This enables an accurate and optimal detection ofvariations in a rotation around a vertical axis as caused by bloodcoagulation. Accordingly, it is preferred that the electrical circuit iscapable of detecting a rotation of the rotatable capacitor elementaround the vertical axis of at least +/−2° with an accuracy of at least0.2° in a time frame of at most 5 seconds.

Preferably, (each of) the capacitor element(s) comprises

-   -   an electrically non-conductive support, which preferably extends        essentially perpendicular to or along the vertical axis, and    -   the at least one electrically conductive element is disposed on        the electrically non-conductive support.

As used herein, “essentially” perpendicular to or along includesdeviations of up to 10°, more preferably up to 7°, even more preferablyup to 5°, still more preferably up to 2° and most preferably up to 1°.For example, the capacitor element has preferably a plate-like,disk-like or cylindrical shape. In particular at least the rotatablecapacitor element has preferably essentially a plate-like, disk-like orcylindrical shape.

Preferably the shape of the fixed capacitor element corresponds to theshape of the rotatable capacitor element. For example, if the rotatablecapacitor element has a plate-like or a disk-like shape also the fixedcapacitor element has preferably a plate-like or a disk-like shape.Preferred exemplified embodiments of such capacitive detection means,wherein the capacitor elements have plate-like or disk-like shapes areshown in FIGS. 4, 5, 6, 8A-D, and 11. For example, if the rotatablecapacitor element has a cylindrical shape, the fixed capacitor elementhas the shape of a (partial) hollow cylinder, which surrounds thecylindrical rotatable capacitor element at least partially—or vice versa(i.e. the fixed capacitor element has a cylindrical shape and therotatable capacitor element has the shape of a (partial) hollowcylinder). A preferred exemplified embodiment of such capacitivedetection means, wherein the rotatable capacitor element has acylindrical shape and the fixed capacitor element has the shape of a(partial) hollow cylinder, is shown in FIG. 9 .

The electrically non-conductive support material of the capacitorelements is preferably a lightweight material, which has preferably lessthan 2.5 g/cm³ mass density. Preferably a capacitor element weighs nomore than 20 g, more preferably no more than 15 g and most preferably nomore than 10 g. More preferably, the capacitive detection means have aweight of 100 g or less, more preferably of 50 g or less, even morepreferably of 25 g or less and most preferably of 15 g or less.

Preferably, the electrically non-conductive support material of thecapacitor elements is selected from PCB (printed circuit board) materialknown in the art (e.g., fibre-enforced epoxy polymer or phenolic resin),plastic, ceramic, glass or carbon fiber.

The electrically conductive element is preferably disposed on theelectrically non-conductive support by photochemical coating,sputtering, metal evaporation, or screen printing.

If more than one electrically conductive element is comprised by acapacitor element, the more than one electrically conductive elementsare preferably insulated from each other and from (all) other parts ofthe capacitive detection means. This can be achieved for example byimplementing the conductive elements as thin layers on non-conductivematerials or by embedding the conductive elements into non-conductivematerial.

Preferably, the at least one fixed capacitor element comprises a sineoscillator electrode (S), a cosine oscillator electrode (C), and/or apickup electrode (P). As used herein, a “sine oscillator electrode (S)”is an electrode, which is connected to an alternating voltage withfrequency f, while a “cosine oscillator electrode (C)” is an electrode,which is connected to another alternating voltage of similar or nearlysimilar frequency f and a phase shift of 90° compared to f. As usedherein, a “pickup electrode (P)” is an electrode, which is coupled to Sand C by electric fields and receives charge fluctuations according tothe alternating voltages at S and C.

For example, the fixed capacitor element may preferably comprise threekinds of electrodes: one or more sine oscillator electrodes (S), one ormore cosine oscillator electrodes (C), and one or more pickup electrodes(P). The S and C electrodes can then preferably be connected to an(oscillating) voltage, e.g. to a rectangular oscillating voltage with a90°-phase shift between S and C. Depending on the shape and/or positionof the conductive element, for example on the rotatable capacitorelement, the capacitance C_(SP) from electrode S to electrode P and thecapacitance C_(CP) from electrode C to electrode P may then be changedin opposite directions. Accordingly, the actual angle of the conductiveelement on the rotatable capacitor element (relative to the conductiveelement on the fixed capacitor element) may then be calculated from thedifference of C_(SP) and C_(CP) after scaling to the sum of C_(SP) andC_(CP). Such a configuration provides a high insensitivity to externalmechanical distortions like distance changes, vibrations, tilting of theaxis, and the like.

In a preferred embodiment the electrical circuit is capable ofgenerating an electrical voltage signal that is proportional to theangular displacement between the (isolated) conductive element(s) on therotatable capacitor element and the fixed capacitor element. To thisend, the fixed capacitor element preferably comprises one or more S, Pand C electrodes, which are preferably arranged in an alternatingmanner, for example in the order S-P-C or in the order C-P-S. Theelectrical circuit comprises a frequency generator, which preferablyprovides alternating electrode voltages at S and C, thereby inducingcharge fluctuations on both electrodes, and, due to the capacitor effectvia one or more conductive element(s) on the rotatable capacitorelement, also at electrode P. Thereby, the fluctuations on P depend onthe electric environment around the electrodes S and C, which changessignificantly during rotation of the conductive element(s) on therotatable capacitor element.

Preferably, direct capacitive charge variations at electrode P induciblewithout the “loop way” over said one or more conductive element(s) onthe rotatable capacitor element are minimized by additional groundedelectrodes located between electrodes S and P, and between electrodes Cand P, respectively, on the fixed capacitor element. Preferably, theelectrical circuit further comprises a charge amplifier, which iscapable of amplifying said charge fluctuations on electrode P.Preferably, the electrical circuit also comprises a synchronizeddetector, which is capable of detecting the (amplified chargefluctuations on electrode P) synchronously to the initial alternatingvoltages at electrodes S and C. In this way, two voltages U_(S) andU_(C) can be generated. Preferably, the electrical circuit furthercomprises two low-pass filters, through which the two voltages U_(S) andU_(C) can be send separately (i.e. each voltage to a separate low-passfilter) to reduce noise. Both resulting voltage signals, U_(S) andU_(C), allow calculation of a signal proportional to the angulardisplacement D of the rotatable capacitor element byD=(U_(S)−U_(C))/U_(S)+U_(C)). The electrical circuit may furthercomprise an ADC (analog/digital converter) in order to digitize theU_(S) and U_(C) signals and to provide those signals as recordable datastream, which may then be further processed digitally.

Other configurations of the array of conductive electrodes on the fixedcapacitor element are also conceivable without changing the abovedescribed general measurement principle. For example, one sineoscillator electrode (S) may be combined on the fixed capacitor elementwith two pickup electrodes (P1 and P2), e.g. at each side of S, whichmay preferably be separated by ground electrodes to prevent directlyinduced charge fluctuations without the loop way via the rotatableconductive element. In this case, the angular movement of saidconductive element results in charge increase at one of the two pickupelectrodes and in charge decrease at the other pickup electrode.

Preferably, the capacitor element comprises more than one electricallyconductive elements and/or more than one (capacitor) electrodes, forexample 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19or 20 or even more than 20 electrically conductive elements and/or 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or evenmore than 20 (capacitor) electrodes. Preferably, the capacitor elementcomprises two electrically conductive elements and/or two (capacitor)electrodes. Preferably, the capacitor element comprises threeelectrically conductive elements and/or three (capacitor) electrodes.Preferably, the capacitor element comprises four electrically conductiveelements and/or four (capacitor) electrodes. Preferably, the capacitorelement comprises five electrically conductive elements and/or five(capacitor) electrodes. Preferably, the capacitor element comprises sixelectrically conductive elements and/or six (capacitor) electrodes.Preferably, the capacitor element comprises seven electricallyconductive elements and/or seven (capacitor) electrodes. Preferably, thecapacitor element comprises eight electrically conductive elementsand/or eight (capacitor) electrodes. Preferably, the capacitor elementcomprises nine electrically conductive elements and/or nine (capacitor)electrodes. Preferably, the capacitor element comprises ten electricallyconductive elements and/or ten (capacitor) electrodes. Preferably, thecapacitor element comprises eleven electrically conductive elementsand/or eleven (capacitor) electrodes. Preferably, the capacitor elementcomprises twelve electrically conductive elements and/or twelve(capacitor) electrodes. Preferably, the capacitor element comprisesthirteen electrically conductive elements and/or thirteen (capacitor)electrodes. Preferably, the capacitor element comprises fourteenelectrically conductive elements and/or fourteen (capacitor) electrodes.Preferably, the capacitor element comprises fifteen electricallyconductive elements and/or fifteen (capacitor) electrodes. Preferably,the capacitor element comprises sixteen electrically conductive elementsand/or sixteen (capacitor) electrodes. Preferably, the capacitor elementcomprises seventeen electrically conductive elements and/or seventeen(capacitor) electrodes. Preferably, the capacitor element compriseseighteen electrically conductive elements and/or eighteen (capacitor)electrodes. Although the above numbers refer in particular to the sum ofall electrically conductive elements and/or of all (capacitor)electrodes present on one single capacitor element, the numbers excludein particular ground electrodes, if present. In general, the higher thenumber of electrically conductive elements/(capacitor) electrodes, theless sensitive the detection means for undesired interferences impairingmeasurement accuracy, such as tilting of the shaft.

Preferably, the at least one fixed capacitor element comprises onesingle sine oscillator electrode (S), one single cosine oscillatorelectrode (C), and one single pickup electrode (P). More preferably, theone single sine oscillator electrode (S), the one single cosineoscillator electrode (C), and the one single pickup electrode (P) aredisposed on the support in an alternating manner, for example in theorder S-P-C or in the order C-P-S. In this case, the rotatable capacitorelement comprises preferably one single conductive element. Anexemplified embodiment of such a configuration is shown in FIG. 8A.

Preferably, the at least one fixed capacitor element comprises at leasttwo sine oscillator electrodes (S), at least two cosine oscillatorelectrodes (C), and at least two pickup electrodes (P). More preferably,the at least two sine oscillator electrodes (S), the at least two cosineoscillator electrodes (C), and the at least two pickup electrodes (P)are disposed on the support in an alternating manner, for example in theorder S-P-C//S-P-C etc. or in the order C-P-S//C-P-S etc. In this case,the rotatable capacitor element comprises preferably at least twoconductive elements, which are preferably evenly distributed on therotatable capacitor element, for example two conductive elementspositioned opposite to each other (180°). Accordingly, the groups of oneS electrode, one C electrode and one P electrode are preferably arrangedon the fixed capacitor element in a corresponding manner, i.e. alsoevenly distributed, for example two groups of one S electrode, one Celectrode and one P electrode are positioned opposite (180°) to eachother. An exemplified embodiment of such a configuration is shown inFIG. 8B.

Preferably, the at least one fixed capacitor element comprises at leastthree sine oscillator electrodes (S), at least three cosine oscillatorelectrodes (C), and at least three pickup electrodes (P). Morepreferably, the at least three sine oscillator electrodes (S), the atleast three cosine oscillator electrodes (C), and the at least threepickup electrodes (P) are disposed on the support in an alternatingmanner, for example in the order S-P-C//S-P-C//S-P-C etc. or in theorder C-P-S//C-P-S//C-P-S etc. In this case, the rotatable capacitorelement comprises preferably at least three conductive elements, whichare preferably evenly distributed on the rotatable capacitor element,for example three conductive elements positioned in a 120° angle to eachother. Accordingly, the groups of one S electrode, one C electrode andone P electrode are preferably arranged on the fixed capacitor elementin a corresponding manner, i.e. also evenly distributed, for examplethree groups of one S electrode, one C electrode and one P electrode arepositioned in a 120° angle to each other. An exemplified embodiment ofsuch a configuration is shown in FIG. 8C.

Preferably, the at least one fixed capacitor element comprises at leastfour sine oscillator electrodes (S), at least four cosine oscillatorelectrodes (C), and at least four pickup electrodes (P). Morepreferably, the at least four sine oscillator electrodes (S), the atleast four cosine oscillator electrodes (C), and the at least fourpickup electrodes (P) are disposed on the support in an alternatingmanner, for example in the order S-P-C//S-P-C//S-P-C//S-P-C etc. or inthe order C-P-S//C-P-S//C-P-S//C-P-S etc. In this case, the rotatablecapacitor element comprises preferably at least four conductiveelements, which are preferably evenly distributed on the rotatablecapacitor element, for example four conductive elements positioned in a90° angle to each other. Accordingly, the groups of one S electrode, oneC electrode and one P electrode are preferably arranged on the fixedcapacitor element in a corresponding manner, i.e. also evenlydistributed, for example four groups of one S electrode, one C electrodeand one P electrode are positioned in a 90° angle to each other.

Preferably, the at least one fixed capacitor element comprises at leastfive sine oscillator electrodes (S), at least five cosine oscillatorelectrodes (C), and at least five pickup electrodes (P). Morepreferably, the at least five sine oscillator electrodes (S), the atleast five cosine oscillator electrodes (C), and the at least fivepickup electrodes (P) are disposed on the support in an alternatingmanner, for example in the order S-P-C//S-P-C//S-P-C//S-P-C//S-P-C etc.or in the order C-P-S//C-P-S//C-P-S//C-P-S//C-P-S etc. In this case, therotatable capacitor element comprises preferably at least fiveconductive elements, which are preferably evenly distributed on therotatable capacitor element, for example five conductive elementspositioned in a 72° angle to each other. Accordingly, the groups of oneS electrode, one C electrode and one P electrode are preferably arrangedon the fixed capacitor element in a corresponding manner, i.e. alsoevenly distributed, for example five groups of one S electrode, one Celectrode and one P electrode are positioned in a 72° angle to eachother.

Preferably, the at least one fixed capacitor element comprises at leastsix sine oscillator electrodes (S), at least six cosine oscillatorelectrodes (C), and at least six pickup electrodes (P). More preferably,the at least six sine oscillator electrodes (S), the at least six cosineoscillator electrodes (C), and the at least six pickup electrodes (P)are disposed on the support in an alternating manner, for example in theorder S-P-C//S-P-C//S-P-C//S-P-C//S-P-C//S-P-C etc. or in the orderC-P-S//C-P-S//C-P-S//C-P-S//C-P-S//C-P-S etc. In this case, therotatable capacitor element comprises preferably at least six conductiveelements, which are preferably evenly distributed on the rotatablecapacitor element, for example six conductive elements positioned in a60° angle to each other. Accordingly, the groups of one S electrode, oneC electrode and one P electrode are preferably arranged on the fixedcapacitor element in a corresponding manner, i.e. also evenlydistributed, for example six groups of one S electrode, one C electrodeand one P electrode are positioned in a 60° angle to each other. Anexemplified embodiment of such a configuration is shown in FIG. 8D.

As described above, the at least one fixed capacitor element preferablycomprises at least one ground electrode located between the differenttypes of electrodes (e.g., S, C, and P electrodes or S, P1 and P2electrodes), for example (i) between a sine oscillator electrode (S) anda pickup electrode (P); and/or (ii) between a cosine oscillatorelectrode (C) and a pickup electrode (P).

In a third aspect, the present invention also provides a capacitivedetection means for detecting variations in a rotation around a verticalaxis caused by blood coagulation comprising

-   -   a rotatable dielectric element, which is capable of rotating        around the vertical axis and which does not have a circular        shape with the vertical axis as center;    -   two fixed capacitor elements; and    -   an electrical circuit, preferably connected to a fixed capacitor        element;

wherein each of the two fixed capacitor elements comprises at least oneelectrically conductive element; the two fixed capacitor elements arearranged such that the electrically conductive elements of the capacitorelements face each other; and the dielectric element is at leastpartially placed between the two fixed capacitor elements.

This Capacitive detection means differs from the above describedcapacitive detection means (according to the second aspect of thepresent invention) in particular in that the rotatable element is not acapacitor element as described above, but a dielectric element, which isat least partially placed between two fixed capacitor elements. Thefunctional principle is quite similar to the above described capacitivedetection means according to the second aspect of the present invention:In general, the electrically conductive elements of the two fixedcapacitor elements, which face each other (as described above in thecontext of the second aspect of the invention), function in a similarmanner as the two conductive plates of a parallel-plate capacitor. Todetect a rotation, a rotatable dielectric element is used, which is atleast partially placed between the two fixed capacitor elements. By suchan arrangement, a rotation of the rotatable dielectric elementinfluences the capacitance formed by the two fixed capacitor elements.To this end, the rotatable dielectric elements can have any shape,except for a circular shape with the vertical axis (i.e. the rotationaxis) as center. The reason is that a rotation (or a variation in therotation) can be detected by a variation in the capacitance (or bycharge fluctuation), however, the rotation of an element having acircular shape with the rotation axis as center would not result in avariation in the capacitance (or by charge fluctuation).

Since the functional principle of the third aspect of the presentinvention is very similar to that of the second aspect of the presentinvention, most of the definitions and preferred embodiments outlinedabove for the second aspect also apply to the third aspect.

For example, the electrical circuit is generally as described above inthe context of the second aspect. However, since according to the thirdaspect, two fixed capacitor elements are present, both comprising atleast one electrically conductive element, the electrical circuit ispreferably connected to both fixed capacitor elements, in particular tothe at least one electrically conductive element of both fixed capacitorelements.

As used herein, the term “dielectric element” refers to an elementcomprising or consisting of a dielectric material. A dielectric materialis an electrical insulator that can be polarized by an applied electricfield. Preferably, the dielectric material is a solid dielectricmaterial. Solid dielectrics are perhaps the most commonly useddielectrics in electrical engineering, and many solids are very goodinsulators. Some examples include porcelain, glass, and most plastics.Preferred solid dielectric materials are those used in the manufactureof capacitors. Preferred examples of a dielectric material include apolymer material, such as polyethylene (PE) or polytetrafluorethylene(PTFE); a ceramic material, such as steatite; a glass material,aluminium oxide; mica; silicon dioxide; and any combination thereof.

Preferably, the dielectric element has essentially a disk-like orplate-like shape, which preferably extends essentially perpendicular tothe vertical axis. As used herein, “essentially” perpendicular includesdeviations of up to 10°, more preferably up to 7°, even more preferablyup to 5°, still more preferably up to 2° and most preferably up to 1°.As described above, the dielectric element may have any shape as long asit does not have a circular shape with the vertical axis as center.Accordingly, the dielectric element may have the shape of a quadranglesuch as a square or a triangle, a circle (having a center which is notthe rotation axis), a segment of a circle, or an ellipse. Preferably,the dielectric element has a “balanced” shape to enable steady rotation(i.e., without imbalance) around the vertical axis. For example, thedielectric element may have the shape of two (or more) oppositelyarranged circle segments, triangles or quadrangles. A preferredexemplary embodiment thereof is shown in FIG. 10 .

The rotatable dielectric element is capable of rotating around thevertical axis (i.e. the axis around which a rotation is to be detected),whereas the two fixed capacitor element are fixed, i.e. stationary. Tothis end, the rotatable dielectric element can preferably be attached toa shaft of an apparatus for measuring the coagulation characteristics ofa sample, which shaft is rotatable around the vertical axis (andpreferably extends along the vertical axis), such that a rotation of theshaft causes a rotation of the rotatable dielectric element and/or viceversa. The fixed capacitor elements may then be attached to anystationary/immobile component(s) of the apparatus, for example such thatthey are essentially in parallel to each other and to the rotatabledielectric element.

As described for the second aspect, the electrically conductive elementsof the capacitor elements can have any shape, except for a circularshape with the vertical axis (i.e. the rotation axis) as center.Accordingly, the electrically conductive elements of the capacitorelements may have the shape of a spot, a quadrangle such as a square ora triangle, a circle (having a center which is not the rotation axis), asegment of a circle, or an ellipse. Most preferably the electricallyconductive element(s) of the capacitor elements have essentially theshape of circle segments or blunt circle segments, for example as shownin FIG. 8A-D. It is also particularly preferred that the electricallyconductive element(s) of the capacitor elements have essentially theshape of a triangle or quadrangle (e.g., a rectangle, square ortrapezoid), for example as shown in FIG. 9 .

One single electrically conductive element may comprise (or form) one ormore (capacitor) electrodes. Preferably, one single electricallyconductive element forms one single (capacitor) electrode.

Preferably, the electrically conductive elements comprise (morepreferably they are made of) a material having an electric conductivityof at least 5·10⁴ S/m. Although such conductor materials include metals,electrolytes, superconductors, semiconductors, plasmas and somenonmetallic conductors such as graphite and conductive polymers, solidconductor materials are generally preferred for the electricallyconductive element. Preferred examples of such solid conductor materialsinclude metals (most preferably copper, silver and aluminium) and metalalloys;

superconductor materials such as metallic superconductors (e.g.magnesium diboride), A15 phases (e.g. vanadium-silicon,vanadium-gallium, niobium-germanium, and niobium-tin), and ceramic andiron-based superconductors (e.g. La_(1.85)Ba_(0.15)CuO₄, and YBCO(Yttrium-Barium-Copper-Oxide)); semiconductors such as silicon,germanium, gallium arsenide, silicon carbide, gray tin, gray selenium,tellurium, boron nitride, boron phosphide, boron arsenide, and the like;and graphite. More preferably, the material comprised by theelectrically conductive element (preferably, of which the electricallyconductive element is made of) is a metal, a metal alloy, ametal-containing material such as conductive silver paste, graphite,graphene, a conductive polymer (e.g., polyaniline or doped polypyrrole),or a doped semiconductor with increased conductivity (e.g.,phosphor-doped silicon or arsenic-doped germanium), or any combinationthereof.

Preferably, the two fixed capacitor elements are arranged in anessentially parallel manner (as described above) to each other and tothe rotatable dielectric element. Preferably, the capacitor elementshave essentially a plate-like or disk-like shape as described above:Preferably the shape of the fixed capacitor element corresponds to theshape of the rotatable capacitor element. For example, if the rotatablecapacitor element has a plate-like or a disk-like shape also the fixedcapacitor element has preferably a plate-like or a disk-like shape.Preferred exemplified embodiments of such capacitive detection means,wherein the capacitor elements have plate-like or disk-like shapes areshown in 10.

Preferably, the electrically conductive elements have an area size of atleast 25 mm², more preferably at least 35 mm², even more preferably atleast 42 mm², and most preferably at least 50 mm². It is also preferredthat the distance between each of the fixed capacitor elements and therotatable dielectric element is no more than 2 mm, more preferably nomore than 1.5 mm, even more preferably no more than 1 mm. It is alsopreferred that the excitation/detection voltage frequency is at least 1kHz, preferably at least 2 kHz, more preferably at least 5 kHz. Therebya rotation of the rotatable capacitor element around the vertical axiscan be detected quickly and with high accuracy.

For example, if all three conditions are fulfilled, i.e. if theelectrically conductive elements have an area size of at least 25 mm²,the distance between each of the fixed capacitor elements and therotatable dielectric element is no more than 2 mm, and if theexcitation/detection voltage frequency is at least 1 kHz, the electricalcircuit will be capable of detecting a rotation of the rotatablecapacitor element around the vertical axis of at least +/−2° with anaccuracy of at least 0.2° in a time frame of at most 5 seconds. Thisenables an accurate and optimal detection of variations in a rotationaround a vertical axis as caused by blood coagulation. Accordingly, itis preferred that the electrical circuit is capable of detecting arotation of the rotatable capacitor element around the vertical axis ofat least +/−2° with an accuracy of at least 0.2° in a time frame of atmost 5 seconds.

Preferably, (each of) the capacitor element(s) comprises

-   -   an electrically non-conductive support, which preferably extends        essentially perpendicular to the vertical axis, and    -   the at least one electrically conductive element is disposed on        the electrically non-conductive support.

The electrically non-conductive support material of the capacitorelements is preferably a lightweight material, which has preferably lessthan 2.5 g/cm³ mass density. Preferably a capacitor element weighs nomore than 20 g, more preferably no more than 15 g and most preferably nomore than 10 g. More preferably, the capacitive detection means have aweight of 100 g or less, more preferably of 50μ or less, even morepreferably of 25μ or less and most preferably of 15 g or less.

Preferably, the electrically non-conductive support material of thecapacitor elements is selected from PCB (printed circuit board) materialknown in the art (e.g., fibre-enforced epoxy polymer or phenolic resin),plastic, ceramic, glass and carbon fiber.

The electrically conductive element is preferably disposed on theelectrically non-conductive support by photochemical coating,sputtering, metal evaporation, or screen printing.

If more than one electrically conductive element is comprised by acapacitor element, the more than one electrically conductive elementsare preferably insulated from each other and from (all) other parts ofthe capacitive detection means. This can be achieved for example byimplementing the conductive elements as thin layers on non-conductivematerials or by embedding the conductive elements into non-conductivematerial.

Preferably, the at least one fixed capacitor element comprises a sineoscillator electrode (S), a cosine oscillator electrode (C), and/or apickup electrode (P) as described above, in the context of the secondaspect.

Preferably, (i) the pickup electrode (P) and (ii) the sine oscillatorelectrode (S) and/or the cosine oscillator electrode (C) are located ondistinct fixed capacitor elements. For example, the upper fixedcapacitor element comprises a pickup electrode (P) and the lower fixedcapacitor element comprises a sine oscillator electrode (S) and/or acosine oscillator electrode (C). Alternatively, it is also preferredthat the lower fixed capacitor element comprises a pickup electrode (P)and the upper fixed capacitor element comprises a sine oscillatorelectrode (S) and/or a cosine oscillator electrode (C). In this way, thegrounded electrodes located in between the S or C and P electrodes arenot required if the S/C electrode(s) and the P electrode(s) are locatedon distinct capacitor elements.

Preferably, a capacitor element comprises more than one electricallyconductive elements and/or more than one (capacitor) electrodes, forexample 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19or 20 or even more than 20 electrically conductive elements and/or 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or evenmore than 20 (capacitor) electrodes as described above.

For example, it is preferred that (i) the upper capacitor elementcomprises one single pickup electrodes (P) and the lower capacitorelement comprises one single sine oscillator electrodes (S) and/or onesingle cosine oscillator electrodes (C) or (ii) the upper capacitorelement comprises one single sine oscillator electrodes (S) and onesingle cosine oscillator electrodes (C) and the lower capacitor elementcomprises one single pickup electrodes (P). Preferably, (i) the uppercapacitor element comprises at least two pickup electrodes (P) and thelower capacitor element comprises at least two sine oscillatorelectrodes (S) and/or at least two cosine oscillator electrodes (C) or(ii) the upper capacitor element comprises at least two sine oscillatorelectrodes (S) and at least two cosine oscillator electrodes (C) and thelower capacitor element comprises at least two pickup electrodes (P).Preferably, (i) the upper capacitor element comprises at least threepickup electrodes (P) and the lower capacitor element comprises at leastthree sine oscillator electrodes (S) and/or at least three cosineoscillator electrodes (C) or (ii) the upper capacitor element comprisesat least three sine oscillator electrodes (S) and at least three cosineoscillator electrodes (C) and the lower capacitor element comprises atleast three pickup electrodes (P). Preferably, (i) the upper capacitorelement comprises at least four pickup electrodes (P) and the lowercapacitor element comprises at least four sine oscillator electrodes (S)and/or at least four cosine oscillator electrodes (C) or (ii) the uppercapacitor element comprises at least four sine oscillator electrodes (S)and at least four cosine oscillator electrodes (C) and the lowercapacitor element comprises at least four pickup electrodes (P).Preferably, (i) the upper capacitor element comprises at least fivepickup electrodes (P) and the lower capacitor element comprises at leastfive sine oscillator electrodes (S) and/or at least five cosineoscillator electrodes (C) or (ii) the upper capacitor element comprisesat least five sine oscillator electrodes (S) and at least five cosineoscillator electrodes (C) and the lower capacitor element comprises atleast five pickup electrodes (P). Preferably, (i) the upper capacitorelement comprises at least six pickup electrodes (P) and the lowercapacitor element comprises at least six sine oscillator electrodes (S)and/or at least six cosine oscillator electrodes (C) or (ii) the uppercapacitor element comprises at least six sine oscillator electrodes (S)and at least six cosine oscillator electrodes (C) and the lowercapacitor element comprises at least six pickup electrodes (P).

It is also preferred that the oscillator electrodes (S), the cosineoscillator electrodes (C), and/or the pickup electrodes (P) are disposedon the support in an alternating manner, for example as described above,in the context of the second aspect. In particular, the sine oscillatorelectrodes (S) and the cosine oscillator electrodes (C) are preferablydisposed on the support in an alternating manner.

In a further aspect, the present invention also provides an apparatusfor measuring the coagulation characteristics of a sample comprising thecapacitive detection means according to the present invention asdescribed above, in particular according to the second and/or thirdaspect of the present invention. Thereby, the apparatus is preferablythe apparatus according to the (first aspect) of the present inventionas described herein. Accordingly, various preferred embodiments of (i)the capacitive detection means according to the present invention asdescribed herein may be combined with various preferred embodiments of(ii) the apparatus according to the present invention as describedherein. Preferred exemplary embodiments of such an apparatus accordingto the present invention comprising the capacitive detection meansaccording to the present invention are shown in FIGS. 4 and 5 .

Temperature Control Device

Viscoelastic measurements are preferably performed at body temperature,i.e. at about 37° C., in order to obtain meaningful results. To thisend, it is preferred if the measurement apparatus comprises atemperature control device, which ensures that throughout themeasurement the temperature of the sample, of the cup or of the cupreceiving element is about 37° C. However, such temperature-controlledmeasurement setups are complicated to realize: Any (even flexible)wiring to a rotating cup induces unwanted counter forces, resulting in adecreased measuring accuracy. In view thereof, the present inventionprovides in a further aspect a contactless temperature control devicewhich allows for contactless temperature sensing and heating/temperaturecontrol of the cup containing the blood sample. The temperature controldevice senses and regulates the temperature of the cup (and the bloodsample contained therein) so as to achieve a certain temperatureresembling or approaching body temperature of a patient, usually in therange between 32 and 39° C.

In a further aspect, the invention thus provides a temperature controldevice for controlling the temperature of a cup and/or of a cupreceiving element while measuring the coagulation characteristics of asample in a thromboelastic measurement apparatus comprising:

-   -   a heating comprising an electromagnetic radiation emitting        element emitting (thermal) radiation with an emission maximum in        the wavelength range from 300 to 3,000 nm;    -   a temperature sensing element for contactless measurement of        (thermal) radiation in the wavelength range from more than 3,000        nm to 30,000 nm; and    -   optionally, controlling means for activating or deactivating the        heating depending on the temperature measured by the temperature        sensing element having an accuracy of at least +/−3° C.

Currently available irradiative temperature sensing and heating devicesused for contactless temperature control (e.g., so-called “pyrometers”basing on the pyro-electric effect, or photodiodes, phototransistors orphotoresistors that are sensitive in the infra-red (IR) range of theelectromagnetic spectrum) are not designed for use in the rather narrowspaces available in a viscoelastic measurement apparatus. The majorproblem within such narrow spaces results from the largely overlappingemission and detection ranges, for example from a direct interference ofheating devices emitting in the IR range with temperature sensorsdetecting in the same IR range, in particular if both are placed withina short distance to each other and/or if they are well surrounded byreflecting (for example metallic) material: Even though the sensor maybe directed at the cup and should measure only the cup temperature, theradiation emitted by the nearby heating is typically not sufficientlyfocused to avoid reflections from other surfaces that falsify themeasurement of the exact cup temperature.

In contrast to other methods known in the art, the temperature controldevice according to the present invention minimizes such directinterference of an electromagnetic radiation source with a thermalradiation sensor by relying on spectral separation, or, in other words,segregation of heating wavelength and detecting wavelength. The presentinventors found that sufficient spectral separation can be achieved byshifting the wavelength (range) used by the heating device to a lowerwavelength range, namely 300-3,000 nm, while contactless thermalradiation sensors usable for temperature detection in the range between20 and 50° C. employ a spectrum above 3,000 nm, usually up to 30,000 nm.

The temperature control device according to the present inventionadvantageously allows control and stabilization of the temperature of ablood sample tested in viscoelastic measurements at a predefined value(usually 37° C., but also lower or higher values) in case conventional(“wired”) heating is impossible. Spectral separation of the wavelengthemitted from the electromagnetic radiation emitting element used as aheating on the one hand, and the wavelength detected by the temperaturesensor on the other hand enables placing the heating element andtemperature sensor close together—which is advantageous in the narrowspace available of viscoelastic measurement apparatuses. It furtherallows the heating and temperature sensor to be almost completelysurrounded by reflective material.

As used herein, the term “thermal radiation” refers to electromagneticradiation generated by the thermal motion of charged particles inmatter. Accordingly, thermal radiation is the emission ofelectromagnetic waves from all matter that has a temperature greaterthan absolute zero. It represents a conversion of thermal energy intoelectromagnetic energy. Thermal radiation is different from thermalconvection and thermal conduction. Examples of thermal radiation includethe visible light and infrared light.

The temperature control device according to the present inventioncomprises a heating element comprising (or consisting of) anelectromagnetic radiation emitting element emitting (thermal) radiationwith its maximum of the spectral radiation distribution in thewavelength range from 300 to 3,000 nm. The electromagnetic radiationemitting element is thus a source of electromagnetic radiation with itsmaximum in the wavelength range from 300 nm to 3,000 nm (3 μm).Preferably, the total radiation energy emitted at wavelengths above 3 μmis less than 20% of the total radiation energy, more preferably it isless than 15%, even more preferably it is less than 10%, and still morepreferably it is less than 5% of the total radiation energy. Mostpreferably, the electromagnetic radiation emitting element doesessentially not emit electromagnetic radiation having a wavelength ofmore than 3,000 nm (3 μm).

More preferably, the electromagnetic radiation emitting element emitselectromagnetic radiation having a wavelength in the wavelength rangefrom 300 to 2,000 nm (2 μm). In this case it is preferred that the totalradiation energy emitted at wavelengths above 2 μm is less than 20% ofthe total radiation energy, more preferably it is less than 15%, evenmore preferably it is less than 10%, and still more preferably it isless than 5% of the total radiation energy. Most preferably, theelectromagnetic radiation emitting element does essentially not emitelectromagnetic radiation having a wavelength of more than 2,000 nm (2μm).

Even more preferably, the electromagnetic radiation emitting elementemits electromagnetic radiation having a wavelength in the wavelengthrange from 300 to 1,500 nm (1.5 μm). In this case it is preferred thatthe total radiation energy emitted at wavelengths above 1.5 μm is lessthan 20% of the total radiation energy, more preferably it is less than15%, even more preferably it is less than 10%, and still more preferablyit is less than 5% of the total radiation energy. Most preferably, theelectromagnetic radiation emitting element does essentially not emitelectromagnetic radiation having a wavelength of more than 1,500 nm (1.5μm).

Still more preferably, the electromagnetic radiation emitting elementemits electromagnetic radiation having a wavelength in the wavelengthrange from 300 to 1,200 nm (1.2 μm). In this case it is preferred thatthe total radiation energy emitted at wavelengths above 1.2 μm is lessthan 20% of the total radiation energy, more preferably it is less than15%, even more preferably it is less than 10%, and still more preferablyit is less than 5% of the total radiation energy. Most preferably, theelectromagnetic radiation emitting element does essentially not emitelectromagnetic radiation having a wavelength of more than 1,200 nm (1.2μm).

Most preferably, the electromagnetic radiation emitting element emitselectromagnetic radiation having a wavelength in the wavelength rangefrom 300 to 1,000 nm (1 μm). In this case it is preferred that the totalradiation energy emitted at wavelengths above 1 μm is less than 20% ofthe total radiation energy, more preferably it is less than 15%, evenmore preferably it is less than 10%, and still more preferably it isless than 5% of the total radiation energy. Most preferably, theelectromagnetic radiation emitting element does essentially not emitelectromagnetic radiation having a wavelength of more than 1,000 nm (1μm).

The advantage of an electromagnetic radiation emitting element emittingradiation in the wavelength range from 300 to 3,000 nm is that suchradiation is distinguishable from the radiation emitted from elementshaving a temperature of 20-50° C. (for example body temperature). Forexample, it is well-known that humans (normal body temperature) radiatemost strongly at a wavelength of about 10,000 nm (10 μm). Or, in moregeneral, according to Planck's law for the spectral distribution ofthermal radiation, a black body having a temperature of about 30-40° C.emits thermal radiation at a maximum of about 10 μm.

Furthermore, an electromagnetic radiation emitting element emittingradiation in the wavelength range from 300 to 3,000 nm is sufficient tomaintain the temperature of the cup/cup receiving element at about bodytemperature when using simple and lower-cost light or IR diodes. Diodes,in particular lower-cost diodes, with a radiation maximum below 300 nmare not able to maintain the required temperature of the cup/cupreceiving element, since the emission energy is too low. On the otherhand, the radiation of diodes, in particular lower-cost diodes, emittingwith a radiation maximum above 3000 nm strongly interferes with thethermal radiation of the cup/cup receiving element and thereforecomplicates the measurement of its exact temperature by remote sensing,if not even making it impossible.

Preferably, the electromagnetic radiation emitting element is anelectromagnetic radiation emitting diode, such as an LED (light-emittingdiode), a near-IR diode or a UV diode. As used herein, the term “LED”(light-emitting diode) includes anorganic light-emitting diodes (LED) aswell as organic light emitting diodes (OLED). In general, diodes, suchas LEDs, have the advantage that they are very small and can be easilyused in the thromboelastic measurement apparatus. An LED typically has awavelength maximum in the visible wavelength range, in particular from450-780 nm. A “near-IR diode” differs from the above described LED inthat it typically has a wavelength maximum in the near infrared(near-IR; NIR) wavelength range, in particular from 780 nm to 3,000 nm(3 μm). A “UV diode” differs from the above described LED in that ittypically has a wavelength maximum in the ultraviolett (UV) wavelengthrange, in particular from 300 nm to 450 nm.

Preferably, the electromagnetic radiation emitting element is an LEDhaving a wavelength maximum in the visible range of the spectrum(450-780 nm, e.g. 660 nm), or a NIR diode having a wavelength maximum inthe near IR of the spectrum (780-3000 nm, e.g. 850 nm). In general,since the output power of a UV diode, an LED, or a near-IR emittingdiode is typically increasing with the wavelength of the emissionmaximum, longer wavelengths of the radiation source may be morebeneficial due to reduced costs of the required components. In viewthereof NIR diodes are preferred electromagnetic radiation emittingelements. On the other hand, however, it is advantageous that thedifference between the emission range (i.e. the wavelength range of theelectromagnetic radiation emitting element) and the detecting/sensingrange (i.e. the wavelength range of the temperature sensing element) isas large as possible. In view thereof, UV diodes and LEDs are preferred.Most preferably, the electromagnetic radiation emitting element providesa compromise between the above outlined requirements, for example theelectromagnetic radiation emitting element is a NIR diode emitting inthe range of 800-1200 nm, for example about 850 nm.

The temperature control device according to the present inventioncomprises a temperature sensing element for contactless measurement ofthermal radiation in the wavelength range from more than 3,000 nm to30,000 nm. Thereby, wires and the like connecting the temperaturesensing element with the (rotatable cup/cup receiving element) areavoided. As described above, it is the major goal of the temperaturesensing element to detect whether or not the cup/cup receiving elementhas the desired temperature, which is usually in the range of 20° C.-50°C., preferably 30° C.-40° C., and most preferably about 37° C. (bodytemperature). According to Planck's radiation law a black body having atemperature in the above specified ranges emits at a wavelength maximumof 9-10 μm (9,000-10,000 nm), which is well within the detection rangeof 3,000-30,000 nm. Accordingly, the temperature sensing element is ableto detect temperatures in the desired range. On the other hand, such adetection range is sufficiently distinct from the wavelength emissionmaxima of the electromagnetic radiation emitting element as describedabove.

Preferably, the temperature sensing element for contactless measurementof thermal radiation has a (maximum) sensitivity in the wavelength rangeof 4,000-30,000 nm. More preferably, the temperature sensing element forcontactless measurement of thermal radiation has a (maximum) sensitivityin the wavelength range of 5,000-25,000 nm. Even more preferably, thetemperature sensing element for contactless measurement of thermalradiation has a (maximum) sensitivity in the wavelength range of5,000-25,000 nm. Still more preferably, the temperature sensing elementfor contactless measurement of thermal radiation has a (maximum)sensitivity in the wavelength range of 6,000-20,000 nm. Most preferably,the temperature sensing element for contactless measurement of thermalradiation has a (maximum) sensitivity in the wavelength range of7,000-15,000 nm.

Preferably, the temperature sensing element is a pyro-electric detector,a photoresistor, or a photodiode.

A pyro-electric detector is an infrared sensitive optoelectroniccomponent which is typically used for detecting electromagneticradiation in a wavelength range from 3 to 14 μm. A pyroelectric detectoris a thermal detector, whereby temperature fluctuations produce a chargechange on the surface of pyroelectric crystals, which produces acorresponding electrical signal. There are different pyroelectricmaterials available, three of which are commonly used in pyroelectricdetectors: DLaTGS, LiTaO₃, and PZT.

A photoresistor (or light-dependent resistor, LDR, or photocell) is alight-controlled variable resistor. A photoresistor is usually made of ahigh resistance semiconductor. In the dark, a photoresistor can have aresistance as high as several megohms (MΩ), while in the light, aphotoresistor can have a resistance as low as a few hundred ohms. Ifincident light on a photoresistor exceeds a certain frequency, photonsabsorbed by the semiconductor give bound electrons enough energy to jumpinto the conduction band. The resulting free electrons (and their holepartners) conduct electricity, thereby lowering resistance. In summary,the resistance of a photoresistor decreases with increasing incidentlight intensity; in other words, it exhibits photoconductivity. Aphotoresistor can thus be applied in light-sensitive detector circuits.Preferred photoresistors include Lead sulphide (PbS) and indiumantimonide (InSb) LDRs (light-dependent resistors) and Ge:Cuphotoconductors.

A photodiode is a semiconductor device that converts light into current.The current is generated when photons are absorbed in the photodiode. Asmall amount of current is also produced when no light is present.Photodiodes using a PIN junction rather than a p-n junction arepreferred due to their increased response speed. Preferred examples ofphotodiodes include lead(II)sulphide diodes, mercury cadmium telluridediodes, and, most preferably, cadmium telluride diodes.

The temperature controlling device according to the present inventionoptionally comprises controlling means for activating or deactivatingthe heating depending on the temperature measured by the temperaturesensing element, which has preferably an accuracy of at least +/−3° C.For example, this can be achieved by using a sensing element with aproven accuracy of less than 2° C. and by an electrical control circuitthat is fast enough to start or stop heating within seconds after atemperature deviation of +/−1° C. has been detected. To achieve doubleaccuracy, the temperature deviation trigger can be for example reducedto +/−0.5° C. and a sensing element with proven accuracy of +/−1° C. canbe used.

Such controlling means are an optional feature, since the control mayalso be performed manually by the user. For example, the temperaturesensing element may be connected to a display and/or to an alarm,informing the user about the actual temperature and/or whether theactual temperature falls below the desired temperature, such that theuser may then activate the heating. However, it is more convenient and,thus, preferred that the temperature controlling device according to thepresent invention comprises controlling means for activating ordeactivating the heating depending on the actual temperature. To thisend, the user may enter a desired temperature or the desired temperaturemay be given, e.g., by the measurement apparatus, for example by certainmeasurement programs. The controlling means can then compare the actualtemperature as detected by the temperature sensing element with thedesired temperature and activate the heating, if the actual temperaturefalls below the desired temperature or deactivate the heating if thedesired temperature was reached. To this end, the controlling means isconnected with (i) the temperature sensing element and (ii) the heatingof the temperature controlling device.

In other words, the controlling means function in principle like asimple control loop, wherein the actual temperature is compared with thedesired temperature and, if both values are identical the heating isdeactivated, whereas if the actual temperature is below the desiredtemperature, the heating is activated.

In a further aspect, the present invention also provides an apparatusfor measuring the coagulation characteristics of a sample comprising thetemperature control device according to the present invention asdescribed above. Preferably, such an apparatus also comprises thecapacitive detection means according to the present invention asdescribed above, in particular according to the second and/or thirdaspect of the present invention. Thereby, the apparatus is preferablythe apparatus according to the (first aspect) of the present inventionas described herein. Accordingly, various preferred embodiments of (i)the temperature control device according to the present invention asdescribed herein; (ii) the capacitive detection means according to thepresent invention as described herein; and/or (iii) the apparatusaccording to the present invention as described herein may be combined.A preferred exemplary embodiment of an apparatus according to thepresent invention comprising temperature controlling device according tothe present invention and the capacitive detection means according tothe present invention are shown in FIG. 11 .

In such an apparatus for measuring the coagulation characteristics of asample comprising the temperature control device according to thepresent invention as described above the heating, in particular theelectromagnetic radiation emitting element, preferably targets the shaftand/or the cup receiver. In general, it is most difficult to directlytarget the cup or the sample without interfering with the blood clottingprocess. The shaft and/or the cup receiver are typically of metal ormetallic material, such that they provide a good thermal conductivity tothe cup, and they are in close vicinity to the cup and the sample, suchthat almost no thermal energy is lost.

Preferably, in such an apparatus, the surface of the shaft and/or of thecup receiver, which is targeted by the electromagnetic radiation emittedfrom the heating, is dark and/or roughened.

Thereby, absorption of the electromagnetic radiation emitted from theheating can be maximized. More preferably, the surface of the shaftand/or of the cup receiver, which is targeted by the electromagneticradiation emitted from the heating, is black and/or roughened.

It is also preferred in such an apparatus that the distance between theheating, in particular the electromagnetic radiation emitting element,and the targeted shaft and/or cup receiving element is no more than 100mm, more preferably no more than 80 mm, even more preferably no morethan 75 mm, still more preferably no more than 60 mm, and mostpreferably no more than 50 mm. It is also preferred that the distancebetween the temperature sensing element and the targeted shaft and/orcup receiving element is no more than 100 mm, more preferably no morethan 80 mm, even more preferably no more than 75 mm, still morepreferably no more than 60 mm, and most preferably no more than 50 mm.

In a further aspect, the present invention also provides the use of thetemperature control device according to the present invention asdescribed above in measuring the coagulation characteristics of asample, which is preferably a blood sample.

Method for Measuring Coagulation Characteristics

In a further aspect, the present invention provides a method formeasuring the coagulation characteristics of a sample by means of anapparatus according to the present invention as described above, themethod comprising the following steps:

-   (a) measuring variations in the rotation around the vertical axis by    means of the detection means;-   (b) converting said measured rotation/variation values to clot    firmness values (CFV) of a viscoelastic measurement curve by the    following formula:

CFV=(A _(o) −A)*100/A _(o)

-   -   wherein A_(o) is the difference between maximum and minimum        signal at the two turning points of the oscillatory movement        before measurement start, and A is the difference between        maximum and minimum signal at the two turning points of the        oscillatory movement at a certain time point during the        measurement; and

-   (c) plotting the CFV's over the corresponding time points to obtain    a measurement graph.

An exemplified measurement graph, which can be obtained by the methodaccording to the present invention, namely in step (c) of the methodaccording to the present invention, is shown in FIG. 3 . Such ameasurement graph provides for example information about the clottingtime (CT), the clot formation time (CFT), the maximum clot firmness(MFT) and maximum lysis. One of the most important parameters is theclotting time (CT), i.e. the time between the time points of (i)(chemically induced) start of blot clotting and (ii) the formation ofthe first long fibrin fibers (indicated by the firmness signal exceedinga defined value). Another important parameter is the clot formation time(CFT), i.e. the time required for the clot firmness to increase from 4to 20 mm. The CFT thus gives a measure for the velocity of the bloodclot formation. The maximum clot firmness a (MCF), i.e. the maximumfirmness achieved by a blood clot during measurement is also of greatdiagnostic importance. Further parameters obtainable fromthromboelastographic measurement curves include the amplitude (A) at acertain time after CT (e.g., A to is the amplitude 10 minutes after CT)and the lysis index (LI) in percent of amplitude reduction when comparedto MCF at a certain time after CT (e.g., LI45 is the ratio between A45and MCF in percent).

Preferably, for the measurement of variations in the rotation around thevertical axis the capacitive detection means according to the presentinvention as described above are used. Thereby, preferred embodiments ofsuch a measurement by using the capacitive detection means as outlinedabove are also preferred in the context of the measurement method.

Furthermore, it is preferred that during the measurement a desiredtemperature, for example in the range of 20-50° C., preferably 30-40° C.and most preferably about 37° C., is achieved and maintained, forexample by means of a temperature control device according to thepresent invention as described herein.

It may also be preferred—in particular if the apparatus is placed in acold environment—that an additional step of pre-heating is included. Insuch a pre-heating step an (external) heating (for example one, two ormore thermos-resistors providing e.g. 5 W power in total) may be used topre-heat non-movable surrounding metal parts of the apparatus (to adesired temperature, e.g., to 37° C.). Such pre-heating by use of an(external) heating may be controlled by a conventional (commerciallyavailable) thermos-regulation unit comprising thermo-resistors and athermocouple as sensor. This has the advantage that the desiredtemperature is quickly achieved and the temperature control deviceaccording to the present invention may then serve for maintaining thedesired temperature during measurement.

BRIEF DESCRIPTION OF THE FIGURES

In the following a brief description of the appended figures will begiven. The figures are intended to illustrate the present invention inmore detail. However, they are not intended to limit the subject matterof the invention in any way.

FIG. 1 is a schematic drawing of the measurement principle for earlyviscoelastic testing devices with optical detection means.

FIG. 2 is a schematic drawing of the measurement principle forviscoelastic testing devices with reduced sensitivity to environmentaldistortions like vibrations or shocks and with optical detection means.

FIG. 3 is an exemplary diagram showing a typical thromboelastometricmeasurement.

FIG. 4 is a schematic drawing of an apparatus according to a firstpreferred exemplary embodiment of the present invention.

FIG. 5 is a schematic drawing of an apparatus according to a secondpreferred exemplary embodiment of the present invention.

FIG. 6 is a schematic drawing of a movement detection system accordingto a preferred exemplary embodiment of the present invention.

FIG. 7 is a schematic drawing of an electrical circuit that creates anelectrical detection signal from the movement detection system of FIG. 6.

FIG. 8 is a schematic drawing of alternative electrode arrangementsregarding number and symmetry.

FIG. 9 is a schematic drawing of an alternative electrode arrangementaccording to a preferred exemplary embodiment of the present invention.

FIG. 10 is a schematic drawing of an alternative electrode arrangementaccording to a further preferred exemplary embodiment of the presentinvention.

FIG. 11 is schematic drawing of a combination of preferred exemplaryembodiments of the present invention.

EXEMPLARY EMBODIMENTS

In the following, the present invention is illustrated in variousexemplary embodiments. However, the present invention shall not to belimited in scope by the specific embodiments described in the following.The exemplary embodiments are given to enable those skilled in the artto more clearly understand and to practice the present invention. Thepresent invention, however, is not limited in scope by the exemplaryembodiments, which are intended as illustrations of selected aspects ofthe invention only, and methods which are functionally equivalent arewithin the scope of the invention. Indeed, various modifications of theinvention in addition to those described herein will become readilyapparent to those skilled in the art from the foregoing description,accompanying figures and the exemplary embodiments below. All suchmodifications fall within the scope of the appended claims.

FIG. 4 shows a schematic drawing of an apparatus (221) according to afirst preferred exemplary embodiment of the present invention (“rotatingcup” embodiment). According to this embodiment shown in FIG. 4 , theapparatus (221) for measuring the coagulation characteristics of asample (201), in particular a “test liquid”, preferably blood (orelements/components, comprises a cup (202) for receiving said sample.Furthermore, the apparatus comprises a pin (203), which can be placedinside the cup (202). In contrast to prior art measurement technologies,in the apparatus shown in FIG. 4 the pin (203) is—preferablydetachably—fixed during the measurement regarding all spatialorientations/directions. This means in particular that the pin (203)cannot move in any direction. This is an important difference to theprior-art technologies described in FIG. 1 and FIG. 2 : In the apparatus(21) shown in FIG. 1 the pin (3) is mounted via a wire (4) and can thusmove in nearly any direction within the cup (2), which makes themeasurement sensitive for shock or vibration. In the prior-arttechnology described in FIG. 2 , the pin (103) is rotatable around thecentral vertical axis of the shaft (106).

In the first preferred exemplary embodiment shown in FIG. 4 the pin(203) can be for example fixed by attaching it to a cover (209). Thecover (209) itself may for example be fixed, e.g. mounted, to a part ofthe apparatus, e.g. to a base support member (220), such as a baseplate. Another possibility to fix the pin is to provide pin and cover inone piece (which includes both, pin and cover) and to attach thatpin/cover piece directly to a base support member, such as a base plate.Preferably, said cup and pin are made of a polymeric material, whichpolymer preferably includes (meth)acrylic and/or styrene monomers, e.g.PMMA, MABS, ABS, PS, or any mixed co-polymer thereof.

According to the first preferred exemplary embodiment shown in FIG. 4 ,the cup (202) is rotatable, in particular around its vertical rotationaxis (212). Preferably, the cup (202) is not movable along the axis(212), but only rotatable around axis (212). The rotation is enabled byproviding a cup receiving element (210), which is connected to a shaft(206) and which is rotatable mounted into a base support member (220),such as a base plate, e.g., by at least one bearing (207). Similar tothe cup (202), also the cup receiving element (210) is preferably notmovable along the axis (212), but only rotatable around axis (212). Inparticular, a complete (full) rotation of 360° around axis (212) is noteven required—typically a small angular movement (“partial” rotation;circular motion) of, for example, +/−2.5° around axis (212) (i.e., inboth directions) is sufficient for viscoelastic testing. Such a(partial) rotation is driven by an elastic coupling element (208), suchas a spring wire, attached to the shaft (206), for example above orbelow said bearing (207).

During coagulation testing the blood sample typically forms a bloodclot. After formation of the clot between cup (202) (e.g., a cuvette)and pin (203), the clot itself is stretched by the movement of the cup(202) relative to the pin (203). The detection of the characteristicparameters of the clot is based on the mechanical coupling of cup (202)and pin (203) by the clot. During a viscoelastic measurement, the pin(203) is fixed and the cup (202) rotates gently and slowly around theaxis (212) by means of the elastic coupling element (208) and the cupreceiving element (210). The movement of the cup (202) can be measuredby various methods, for example by means of capacitive detection means(211), such as capacitor plates. In operation, the pin (203) isstationary and the rotatable shaft (206) and cup (202) placed in the cupreceiver (210) are rotated back and forth by the elastic element (208,e.g. a spring wire), for example in an angular range of about ±5°. Therotation is transmitted by the coupling of the shaft (206) to the cupreceiving element (210). When the blood clot forms an increasing torqueacts against the oscillating movement of the cup (202), such that thecup/cup receiving element is oscillating in a decreased angular range of<±5°. This decrease in angular (oscillating) movement can be detected bysuitable detection means (211) disposed below the pin (203) and cup(202)/cup receiving element (210).

This first preferred exemplary embodiment shown in FIG. 4 allows fillingof the cup (202) with reagent and sample while being placed in the(optionally temperature-controlled) measurement position. It furtheravoids the need to attach a separate cup holder with cup and sample tothe measurement device after filling the sample into the cup and beforemeasurement start (as for example described in U.S. Pat. No. 5,777,215).Additionally, the first preferred exemplary embodiment shown in FIG. 4further avoids the need to put the pin onto a small shaft before themeasurement procedure starts (as for example described in U.S. Pat. No.6,537,819 B2). Both improvements result in easier handling for the userand reduce in this way the risk for potential user mistakes.

Another advantage of the first preferred exemplary embodiment shown inFIG. 4 is that the lower end of the shaft (206) can also be used for amovement detection unit, enabling new options of movement detectiontechnologies (in addition to the prior art optical detection as shown inFIG. 1 ). For example, in the first preferred exemplary embodiment shownin FIG. 4 , field-based detection by means of capacitive detection means(211), such as capacitor plates, e.g. in an oscillatory circuit, may beemployed. Nevertheless, also a movement detection by light beamdeflection would be still applicable in this first embodiment.

In contrast to the existing measurement technologies, in the preferredembodiment shown in FIG. 4 the pin is (optionally detachably) fixed andthus essentially immobile in all orientations. This is in contrast toprior-art apparatuses (see FIG. 1 and FIG. 2 ), where pin can eithermove in any direction (cf. FIG. 1 where the pin (3) is mounted via aspring wire (4)) or is rotatable around the vertical axis (cf. FIG. 2 ).This novel design according to the present invention has the advantageof allowing the filling of the cup with reagent and sample while beingplaced in its measurement position and at the measurement temperature.It thus avoids the filling of the cup outside of the measurementapparatus (and at a different temperature) and subsequently placing itin its measurement position (e.g. as described in U.S. Pat. No.5,777,215). It is also obviates the need to mount the pin to a pin neckprior to measurement (e.g. as described U.S. Pat. No. 6,537,819). Thus,the apparatus enables easier handling and thereby reduces the risk forpotential usage errors. Another advantage of this embodiment is that thedistal end of the shaft is free and can be used for an alternativedetection technology, in particular, for capacitive detection asdescribed herein.

FIG. 5 shows a schematic drawing of an apparatus (321) according to asecond preferred exemplary embodiment of the present invention(“rotating pin” embodiment). According to this embodiment shown in FIG.5 , the cup (302) is now (preferably detachably) fixed, e.g. to a baseplate, by means of a cup receiving element (310). This means inparticular that the cup (302) cannot move in any direction. However, thepin (303) is rotatable, in particular around its vertical rotation axis(312). Preferably, the pin (303) is not movable along the axis (312),but only rotatable around axis (312). Again, in particular a complete(full) rotation of 360° around axis (312) is not even required—typicallya small angular movement (“partial” rotation; circular motion) of, forexample, +/−4° around axis (312) (i.e., in both directions) issufficient for viscoelastic testing. For example, the pin (303) can be(preferably detachably) fixed to a frame (313), which is connected to ashaft (306) and which is rotatable mounted into a base support member(320), such as a base plate, e.g., by at least one bearing (307). Theframe (313) can be formed, for example, by an essentially rectangulararrangement of rods or tubes, e.g. comprising two or, more preferably,four metal rods or tubes, or by an essentially rectangular formed(single) rod or tube, which extends through corresponding openings (323)in the upper plate (322). The openings (323) in the upper plate (322)are preferably shaped such that they allow for an partialrotation/angular movement of the frame (313) of at least +/−2°, morepreferably at least +/−4°. Similar to the embodiment shown in FIG. 4 ,the (partial) rotation (here: of the frame and, thus, the pin) isenabled by an elastic coupling element (308), such as a spring wire,attached to the shaft (306), which is connected to the frame (313). Theelastic coupling element (308) can be mounted above or below saidbearing (307).

Thus, in contrast to the prior art apparatus shown in FIG. 2 , in thesecond preferred exemplary embodiment of the present invention shown inFIG. 5 rotatable fixing of the pin (303) is not realized by a shaft thatis supported by a bearing above the cup/cup receiving element, but by aframe (313) attached to a shaft (306) that is supported by a bearing(307) below the cup/cup receiving element. In this way, the sample (301)can be filled into the cup (302) while being placed in the finalmeasurement position—whereas in measurement apparatuses of the priorart, e.g. as described in U.S. Pat. No. 5,777,215, the bearing ispositioned directly above the cup, which makes filling of the cup in themeasurement position impossible. Moreover, due to the provision of therotating means, such as the ball bearing, below the cup/cup receivingelement (instead of above), the center of mass of the entire apparatusis considerably lower and, thus, the apparatus is less susceptible tovibrations, tilting, and similar environmental influences, which mayotherwise influence the measurement.

In addition, the placement of the rotation means, such as the bearing(307) and/or the spring (308) below the cup/cup receiving elementenables new movement detection means due to the resulting availablespace at the lower end of the shaft (306), similarly to the embodimentin FIG. 4 . Accordingly, movement of the pin may be detected by opticalmeans as described in the prior art (see FIG. 2 ) or by field-baseddetection by means of capacitive detection means (311), such ascapacitor plates, e.g. in an oscillatory circuit.

In summary, also the second embodiment of the present invention asdepicted in FIG. 5 , realizes the three advantages mentioned above forthe first embodiment as shown in FIG. 4 , namely, (i) it allows fillingof the cup (302) with the sample (and, optionally reagents) while beingplaced in the measurement position; (ii) it avoids the need to attach aseparate cup holder, which holds the cup receiving element inmeasurement position after addition of the sample; and (iii) it enablesthe use of new movement detection means, such as capacitor plates. Inaddition, the apparatus' center of mass is considerably lower making theapparatus more robust and more easy to handle.

FIG. 6 shows a preferred embodiment of the detection system according tothe present invention, which may be used in viscoelastic measurementsand which can be easily combined with the apparatus according to thepresent invention, for example with the preferred exemplified embodimentthereof shown in FIG. 4 or with the preferred exemplified embodimentthereof shown in FIG. 5 . FIG. 6 shows schematically a cup (402) with asample (401) and a pin (403). Below the cup (402) is a bearing (407) anda shaft (406), to which an elastic coupling element (408) is attachedfor providing rotation. The lower end of the shaft (406) is connected toa rotatable capacitor element (411 a), which is preferably light-weight.Most preferably, the capacitor element (411 a) is a disk. It is alsopreferred that the rotatable capacitor element (411 a), in particularthe disk, is rotational symmetric to facilitates rotation of therotatable capacitor element (411 a).

Preferably, the rotatable capacitor element (411 a) is attached to thelower end of the shaft (406), such that shaft (406) is essentiallyperpendicular to the rotatable capacitor element (411 a). The rotatablecapacitor element (411 a) has electrically conductive elements (shadedareas in the capacitor element (411 a) shown in FIG. 6 ), which arepreferably arranged in an rotationally symmetric manner. Said capacitorelement (411 a) can be obtained, for example, from standard PCB (printedcircuit board) material, or from special lightweight PCB material knownin the art, e.g. by etching the corresponding electrically conductiveelements out of the conductive layer of the PCB material. Alternatively,said rotatable capacitor element (411 a) can be obtained by applying ametal coating onto a support material, e.g., ceramics (for example byscreen printing using a “mask” to obtain electrically conductiveelements).

In parallel to the rotatable capacitor element (411 a) another capacitorelement (411 b) is provided. In general, a capacitor element refers inparticular to one or more conductive elements arranged on a support.Said capacitor element (411 b) can also be obtained by, for example,etching PCB material or by applying metal to a support material, such asceramics. Said capacitor element (411 b) is fixed, while the rotatablecapacitor element (411 a) follows the rotating movement of shaft (406).In other words, rotatable capacitor element (411 a) typically rotateswith the rotating shaft. Said fixed capacitor element (411 b) iselectrically connected to a circuitry, while the conductive elements onrotatable capacitor element (411 a) are electrically insulated from allother parts and from each other. The movement of the shaft (406) canthus be detected by the relative movement of the capacitor element (411a) (which rotates with shaft (406)) in respect to the fixed capacitorelement (411 b).

The fixed capacitor element (411 b) may for example comprise three kindsof electrodes: Sine oscillator (S), Cosine oscillator (C), and Pickupelectrode (P). The electrodes S and C can then be connected to arectangular oscillating voltage with a 90°-phase shift between S and C.Other phase shifts and/or a frequency shift between the two signals arealso possible. Depending on the angular position of shaft (406) and thecorresponding exact position of the conductive element on the connecteddisk, the capacitance C_(SP) from electrode S to electrode P and thecapacitance C_(CP) from electrode C to electrode P is changed inopposite directions. Accordingly, the actual angle of the rotatableconductive element can be calculated from the difference of C_(SP) andC_(CP) after scaling to the sum of C_(SP) and C_(CP). This scalingprovides high insensitivity to external mechanical distortions likedistance changes, vibrations, tilting of the axis, and the like.

FIG. 7 shows schematically a preferred exemplary embodiment of acircuitry forming an oscillating circuit to measure capacitancedifferences between the electrodes S and C and the pickup electrode P.Electrodes “S”, “C”, and “P” are electrically conductive elements of thefixed electrode, whereas “Z” represents an electrically conductiveelement of the rotatable capacitor element. In this way, an electricalvoltage signal can be generated that is proportional to the angulardisplacement between the isolated conductive layers on the rotatablecapacitor element (411 a) and the fixed capacitor element (411 b), e.g.shown in FIG. 6 : The alternating electrode voltages at S and C asprovided by a frequency generator (14) induce charge fluctuations onboth electrodes, and, due to the capacitor effect, also at electrode P.Thereby, the fluctuations on P depend on the electric environment aroundthe electrodes S and C, which changes significantly by rotating theconductive element(s) Z on said disk. In particular, direct capacitivecharge variations at P inducible without the loop way over saidconductive elements can optionally be minimized by additional groundedelectrodes between electrodes S and P, and between electrodes C and P,respectively.

Said charge fluctuations on electrode P can be amplified by a chargeamplifier (15) and detected synchronously to the initial alternatingvoltages at electrodes S and C in a synchronized detector (16). In thisway, two voltages U_(S) and U_(C) are generated and subsequently sendthrough separated low-pass filters to reduce noise. Both resultingvoltage signals, X and Y, allow calculation of a signal proportional tothe angular displacement D of the capacitor element (11 a) byD=(X−Y)/X+Y). To provide this signal as recordable data stream, theinitial signals X and Y could be also digitized in an ADC(analog/digital converter) and then further processed digitally.

Other configurations in the fixed array of conductive electrodes arealso conceivable without changing the general measurement principle. Forexample, one sine oscillator electrode (S) could be combined with twopickup electrodes (P1 and P2) at each side of S, separated again byground electrodes to prevent directly induced charge fluctuationswithout the loop way via the rotatable conductive elements. In thiscase, the angular movement of said conductive elements would result incharge increase at one of the two pickup electrodes and in chargedecrease at the other pickup electrode.

FIG. 8A-D shows preferred exemplary embodiments of the arrangement ofthe electrodes on the rotatable capacitor element (11 a, 11 a′, 11 a″,11 a′″; left) and on the fixed capacitor element (11 b, 11 b′, 11 b″, 11b′″; right). The exemplary embodiment shown in FIG. 8A represents thesimplest approach of electrode arrangement. Such an arrangement may besensitive to even slight tilting of the shaft holding the rotatableelectrodes. The exemplary embodiment shown in FIG. 8B is insensitive totilting of the shaft in one direction (i.e., tilting in the directionswhere the electrodes are placed), but not insensitive to tilting inother directions. The exemplary embodiment shown in FIG. 8C is thesimplest approach that is insensitive to tilting of the shaft in anypossible direction parallel to the electrodes plane. However, electrodescover not yet all of the available space on the rotating disk. Theexemplary embodiment shown in FIG. 8D is insensitive to shaft tilting inany direction and makes use of nearly all available space on therotating disk for electrodes. This approach increases the resultingsignal and considerably improves therefore the signal to noise ratio ofthe setup.

In summary, there is a high variability in number, arrangement andsymmetry of employed electrodes. As a general principle, the precisionand insensitivity against external distortions is improved by increasingthe electrode number for each type S, C, and P from 1 to at least 3.

FIG. 9 shows another preferred exemplary embodiment of the capacitorelements (511 a, 511 b) of a detection system according to the presentinvention, wherein the capacitor elements (511 a, 511 b) have acylindrically shaped geometry. In cylindrical geometry, the conductiveelements can be for example directly printed (or metal-evaporated) on arotating, nonconductive shaft (506) to save weight. Alternatively,another cylindrical element serving as rotatable capacitor element (511a) may be attached to the shaft (506), for example a sleeve made ofnon-conductive material. Electrodes of type S, C and P are placed at afixed position surrounding the rotating axis (512). The number ofelectrodes is again variable.

FIG. 10 shows another preferred exemplary embodiment of the detectionsystem according to the present invention, wherein the dielectricvariation of the capacitance between fixed capacitor elements (611 a,611 b) is used. Instead of using a rotating capacitor element relativeto a fixed capacitor element to induce variations in capacitance asdescribed above, in the present exemplary embodiment the electrodes Sand C are aligned face-to-face to an electrode P in fixed positions. Inthis setup, the axis (612) is equipped with a segmented disk made of adielectric material (617) that moves between the electrodes independence of the angular orientation of the axis. The dielectricmaterial can be for example a polymer material like polyethylene (PE) orpolytetrafluorethylene (PTFE), a ceramic material like steatite, oranother dielectric material like aluminum oxide, mica, or silicondioxide.

FIG. 11 shows a schematic drawing of an apparatus (721) according to apreferred exemplary embodiment of the present invention equipped with atemperature control device (718, 719) according to the presentinvention. In general, the apparatus (721) corresponds to the preferredexemplary embodiment shown in FIG. 4 (see above), however, additionallyequipped with a temperature control device (718, 719). Accordingly, theapparatus (721) comprises a cup (702) with a sample (701), which isattached to a cup receiving element (710). The immobile pin (703) isfixed to a cover (709). The cup receiving element (710) is attached to ashaft (706), which is rotatable mounted into a base support member(720), such as a base plate, e.g., by at least one bearing (707).Accordingly, the cup receiving element (710) and the cup (702) can(partially) rotate around axis (712). Such a (partial) rotation isdriven by an elastic coupling element (708), such as a spring wire,attached to the shaft (706), for example above or below said bearing(707).

A heating (719), in particular a radiation element, which emitselectromagnetic radiation in the wavelength range below 3 μm (3000 nm),more preferably below 1 μm (1000 nm), is placed in close vicinity(preferably not more than 75 mm distance) of the shaft (706) and/or thecup-receiving element (710). Such a radiation element (719) may be, forexample, a light emitting diode (preferably having a wavelength range450-780 nm), a near-IR diode (preferably having a wavelength range780-1500 nm), or a UV diode (preferably having a wavelength range300-450 nm). A portion of the emitted energy (indicated by the dottedarrow in FIG. 11 ) is converted into heat in the shaft (706) and/or inthe cup-receiving element (710) by absorption. This energy absorption isdependent on surface properties: the more dark (e.g., black) and therougher the surface of the shaft (706) and/or the cup-receiving element(710) is/are made, the more radiation can be absorbed. In thetheoretical approximation of an ideally “black” body, radiationabsorption is independent from the wavelength.

The upper cut-off of the spectral range of emitted radiation (wavelengthof 3 μm, preferably 1 μm) is important, because the emitted radiationshould not interfere with the spectral range of thermal radiationaccording to Planck's law. This law describes that thermal radiation isemitted only in the range above 3 μm for an (ideally black) body at atemperature between 30 and 40°. The thermal radiation (as indicated bythe dotted arrow in FIG. 11 ) directed to the shaft (706) and/or thecup-receiving element (710) can then be used to measure the temperatureof the shaft (706) and/or the cup-receiving element (710) in a nearby(preferably maximum 75 mm distance) temperature sensor (718). Thetemperature sensor (718) may be, for example, a (calibrated) photodiodeor photoresistor, or a pyro-electric sensor. Usually, these sensorsabsorb thermal radiation only in a certain spectral range that dependson the temperatures to be measured. In particular, sensors intended tomeasure temperatures between 20 and 50° C. typically have a spectralsensitivity in the range between 3 μm and 30 μm, because the thermalradiation according to Planck's law on thermal radiation peaks in thisrange.

For example, a near-IR diode with emission maximum around 850 nm (2 Wtotal power, OSRAM SSH4715AS) was used as a heating (719) and apyro-electric detector with spectral sensitivity between 5.5 and 14 um(MELEXIS MLX 90615) was used as temperature sensor (719). Shaft (706)and cup receiving element (710) were blackened by conventionalblackboard color to increase absorption of thermal radiation.Non-movable surrounding metal parts were heated to 37° C. by 2conventional thermo-resistors (5 W power in total) and controlled tomaintain this value by a conventional thermo-regulation consisting ofsaid thermo-resistors and a thermocouple as sensor. The IR diode enabledadditional heating of the cup receiving element and the cup from 35.5°C. (as achieved by thermal radiation from the surrounding non-movableparts) to 37° C. (as required to perform a thromboelastometricmeasurement at typical body temperature) within less than 30 seconds. Analternative radiation source, a light emitting diode with emissionmaximum at 660 nm (CREE, Xlamp XP, XPEPHR-L 1-0000-00901) and an averageoutput power of 0.35 W, was also able to heat the cup receiving element(710) and cup (702) from 35.5° C. to 37° C. with less than 30 seconds.The maximum achievable temperature difference between surrounding metalparts and cup was about 16° C. for the diode emitting at 850 nm maximumand about 12° C. for the diode emitting at 660 nm maximum.

What is claimed is:
 1. A capacitive detection means for detectingvariations in a rotation around a vertical axis caused by bloodcoagulation, comprising: a rotatable capacitor element capable ofrotating around the vertical axis; at least one fixed capacitor element;and an electrical circuit, which is preferably connected to the at leastone fixed capacitor element; wherein each of the capacitor elementscomprises at least one electrically conductive element, which does nothave a circular shape with the vertical axis as a center, and whereinthe rotatable capacitor element and the at least one fixed capacitorelement are arranged such that the at least one electrically conductiveelement of the rotatable capacitor element faces the at least oneelectrically conductive element of the at least one fixed capacitorelement; wherein the electrical circuit is capable of detecting arotation of the rotatable capacitor element around the vertical axis ofat least +/−2° with an accuracy of at least 0.2° in a time frame of atmost 5 seconds.
 2. The capacitive detection means according to claim 1,wherein at least one of the capacitor elements comprises an electricallynon-conductive support, which preferably extends essentiallyperpendicularly to the vertical axis and wherein the at least oneelectrically conductive element of said at least one of the capacitorelements is disposed on the support.
 3. The capacitive detection meansaccording to claim 1, wherein the at least one fixed capacitor elementis arranged essentially in parallel to the rotatable capacitor element.4. The capacitive detection means according to claim 1, whereinrotatable capacitor element has essentially a plate-like, disk-like orcylindrical shape.
 5. The capacitive detection means according to claim1, wherein the at least one fixed capacitor element comprises a sineoscillator electrode (S), a cosine oscillator electrode (C), and apickup electrode (P).
 6. The capacitive detection means according toclaim 5, wherein the at least one fixed capacitor element comprises atleast three sine oscillator electrodes (S), at least three cosineoscillator electrodes (C), and at least three pickup electrodes (P). 7.The capacitive detection means according to claim 1, further comprisingat least one ground electrode (G) located on the at least one fixedcapacitor element (i) between a sine oscillator electrode (S) and apickup electrode (P); or (ii) between a cosine oscillator electrode (C)and a pickup electrode (P).
 8. The capacitive detection means accordingto claim 1, wherein the rotatable capacitor element can be attached to ashaft of an apparatus for measuring the coagulation characteristics of asample, which shaft is rotatable around the vertical axis, such that arotation of the shaft causes a rotation of the rotatable capacitorelement and/or vice versa.
 9. A capacitive detection means for detectingvariations in a rotation around a vertical axis caused by bloodcoagulation, comprising: a rotatable dielectric element, which iscapable of rotating around the vertical axis and which does not have acircular shape with the vertical axis as center; two fixed capacitorelements; and an electrical circuit, preferably connected to a fixedcapacitor element; wherein each of the two fixed capacitor elementscomprises at least one electrically conductive element; the two fixedcapacitor elements are arranged such that the electrically conductiveelements of the capacitor elements face each other; and the dielectricelement is at least partially placed between the two fixed capacitorelements; wherein the electrical circuit is capable of detecting arotation of the rotatable dielectric element around the vertical axis ofat least +/−2° with an accuracy of at least 0.2° in a time frame of atmost 5 seconds.
 10. The capacitive detection means according to claim 9,wherein the capacitor elements comprise an electrically non-conductivesupport, which preferably extends essentially perpendicularly to thevertical axis and at least one electrically conductive element disposedon the support.
 11. The capacitive detection means according to claim 9,wherein the two fixed capacitor elements are arranged in an essentiallyparallel manner to each other and to the rotatable dielectric element.12. The capacitive detection means according to claim 9, wherein thecapacitor elements have essentially a plate-like or disk-like shape. 13.The capacitive detection means according to claim 9, wherein thecapacitor elements comprise at least one sine oscillator electrode (S),at least one cosine oscillator electrode (C), and/or at least one pickupelectrode (P).
 14. The capacitive detection means according to claim 13,wherein the upper capacitor element comprises a pickup electrode (P) andthe lower capacitor element comprises a sine oscillator electrode (S),and a cosine oscillator electrode (C).
 15. The capacitive detectionmeans according to claim 14, wherein the upper capacitor elementcomprises at least three pickup electrodes (P) and the lower capacitorelement comprises at least three sine oscillator electrodes (S), and atleast three cosine oscillator electrodes (C).
 16. The capacitivedetection means according to claim 13, wherein the upper capacitorelement comprises a sine oscillator electrode (S) and a cosineoscillator electrode (C) and the lower capacitor element comprises apickup electrode (P).
 17. The capacitive detection means according toclaim 16, wherein the upper capacitor element comprises at least threesine oscillator electrodes (S) and at least three cosine oscillatorelectrodes (C) and the lower capacitor element comprises at least threepickup electrodes (P).
 18. The capacitive detection means according toclaim 9, wherein the rotatable dielectric element can be attached to ashaft of an apparatus for measuring the coagulation characteristics of asample, which shaft is rotatable around the vertical axis, such that arotation of the shaft causes a rotation of the rotatable dielectricelement and/or vice versa.
 19. The capacitive detection means accordingto claim 9, wherein the dielectric element has essentially a disk-likeor plate-like shape.
 20. An apparatus for measuring the coagulationcharacteristics of a sample comprising the capacitive detection meansaccording to claim
 9. 21. A temperature control device for controllingthe temperature of a cup and/or of a cup receiving element whilemeasuring the coagulation characteristics of a sample in athromboelastic measurement apparatus, comprising: a heater comprising anelectromagnetic radiation emitting element emitting radiation with anemission maximum in the wavelength range from 300 to 3,000 nm; atemperature sensing element for contactless measurement of thermalradiation in the wavelength range from more than 3,000 nm to 30,000 nm;and optionally, controlling means for activating or deactivating theheater depending on the temperature measured by the temperature sensingelement, which has preferably an accuracy of at least +/−3° C.
 22. Thetemperature controlling device according to claim 21, wherein theelectromagnetic radiation emitting element is a diode.
 23. Thetemperature controlling device according to claim 22, wherein the diodeis an LED or a near-IR diode.
 24. The temperature controlling deviceaccording to claim 21, wherein the temperature sensing element is apyro-electric detector, a photoresistor, or a photodiode.
 25. Thetemperature controlling device according to claim 21, wherein thecontrolling means comprise a feedback loop for the heater current,voltage, or pulse width.
 26. An apparatus for measuring the coagulationcharacteristics of a sample comprising the temperature control deviceaccording to claim
 21. 27. The apparatus according to claim 26, furthercomprising a capacitive detection means for detecting variations in arotation around a vertical axis caused by blood coagulation, thecapacitive detection means comprising: a rotatable capacitor elementcapable of rotating around the vertical axis; at least one fixedcapacitor element; and an electrical circuit, which is preferablyconnected to the at least one fixed capacitor element; wherein each ofthe capacitor elements comprises at least one electrically conductiveelement, which does not have a circular shape with the vertical axis asa center, and wherein the rotatable capacitor element and the at leastone fixed capacitor element are arranged such that the at least oneelectrically conductive element of the rotatable capacitor element facesthe at least one electrically conductive element of the at least onefixed capacitor element; wherein the electrical circuit is capable ofdetecting a rotation of the rotatable capacitor element around thevertical axis of at least +/−2° with an accuracy of at least 0.2° in atime frame of at most 5 seconds.